Synthesis of a Chiral Quaternary Carbon Center Bearing a Fluorine Atom: Enantio‐ and Diastereoselective Guanidine‐Catalyzed Addition of Fluorocarbon Nucleophiles

Abstract

The CÀF bond is highly polarized and its unique properties are often understood by considering its stereoelectronic interactions with neighboring bonds or lone pairs of electrons. [1] Whereas natural organofluoro compounds are rare, synthetic fluorinated compounds are useful in areas such as materials, agrochemicals, pharmaceuticals, and fine chemicals. [2] Strategic fluorination is commonly used in contemporary medicinal chemistry to improve metabolic stability, bioavailability, and protein-drug interactions. [3] The replacement of metabolically active hydrogen atoms with fluorine atoms increases the in vivo lifetime of drugs. As such, fluorine-containing compounds are ubiquitous in blockbuster drugs, for example, fluoxetine (antidepressant), atorvastatin (cholesterol-lowering), and ciprofloxacin (antibacterial). The specific incorporation of fluorine in a regio-and stereoselective manner has thus become the most pivotal consideration in the synthesis of fluorinated compounds. To date, both nucleophilic fluorination [4] and electrophilic fluorination [5] methods have been developed.With the huge number of potential applications, asymmetric CÀF bond formation has been become a subject of intense research and has emerged as an important goal in organic chemistry. [6] Hintermann and Togni reported the first example of an enantioselective catalytic electrophilic afluorination using a titanium/taddol complex (taddol = tetraaryl-1,3-dioxolane-4,5-dimethanol) and Selectfluor. [7] The emergence of other stable sources of electrophilic fluorinating agents such as N-fluorobenzenesulfonimide (NFSI) and the use of other metal complexes allowed the scope of asymmetric C À F bond formation to be dramatically expanded. [8] Organocatalytic approaches for asymmetric C À F bond transformation using proline and cinchona alkaloids and their derivatives as catalysts have recently been shown to be a viable alternative. [9] Catalytic enantioselective nucleophilic fluorination is not common; however, one example is the ring opening of epoxides with fluoride sources using salen/ chromium complexes (salen = bis(salicylidene)ethylenediamine) as catalysts. [10] The use of a fluorocarbon nucleophile such as 1-fluorobis(phenylsulfonyl)methane (FBSM) as a synthetic equivalent of monofluoromethane was effectively exploited in a Mitsunobu reaction, [11] Michael reaction, [12a] Mannich reaction, [12b] and palladium-catalyzed allylation. [12c] The amination of 2-fluoro-tert-butyl benzoylacetate under phase-transfer conditions was found to proceed with moderate enantioselectivity. [13] Other novel approaches towards chiral quaternary carbon centers bearing a fluorine atom include the enantioselective decarboxylation of a-fluoro-bketoesters. [14] To the best of our knowledge, a highly enantioselective and diastereoselective reaction using a fluorocarbon nucleophile has not yet been reported.We are keen to develop bicyclic guanidines as general Brønsted base catalysts, and we found that these bases work particularly well with conjugate additi...

Highly Enantio‐ and Diastereoselective Synthesis of β‐Methyl‐γ‐monofluoromethyl‐Substituted Alcohols

“…[12b] Catalyst loading can also be lowered to 5 mol % (entry 7). Next, we investigated the effects of solvent and temperature (entries [8][9][10][11][12][13]. Mesitylene was found as the most suitable solvent, giving 3 a in 95 % ee at 50 8C after 72 h (entry 11).…”

“…tions. [8] Herein, we would like to report the first highly enantio-and diastereoselective synthesis of b-methyl-g-monofluoromethyl-substituted alcohols based on the allylic alkylations between bis(phenylsulfonyl)methane (BSM) or fluorobis(phenylsulfonyl)methane (FBSM) with Morita-Baylis-Hillman (MBH) carbonates.…”

Expanding the Utility of Brønsted Base Catalysis: Biomimetic Enantioselective Decarboxylative Reactions

“…[10c] An excellent alternative strategy is to mimic the polyketide biosynthetic pathway. The bifunctional nature of a bicyclic guanidine [11] catalyst should be appropriate for a proximity-assisted decarboxylative strategy (Scheme 1b).…”

Bicyclic Guanidine‐Catalyzed Direct Asymmetric Allylic Addition of N‐Aryl Alkylidene‐Succinimides

“…As the reaction time increased, the equilibrium shifted towards maleimide 2 and full deuteration was achieved for all protons.Encouraged by this observation, we envisioned a Brønsted-base catalyzed asymmetric allylic addition using N-aryl alkylidene-succinimides as nucleophiles. We have shown previously that chiral guanidine [11] can catalyze a variety of reactions with high enantioselectivities. Herein, we demonstrate that bicyclic guanidine can catalyze the direct asymmetric allylic addition of N-aryl alkylidene-succinimides to imines with high enantioselectivities.Preliminary studies using methylidene-succinimide 1 a revealed that direct allylic addition to N-protected imines resulted in amine 6 g as the only product by an a-addition followed by a 1,3-proton shift (Scheme 1).…”

“…Encouraged by this observation, we envisioned a Brønsted-base catalyzed asymmetric allylic addition using N-aryl alkylidene-succinimides as nucleophiles. We have shown previously that chiral guanidine [11] can catalyze a variety of reactions with high enantioselectivities. Herein, we demonstrate that bicyclic guanidine can catalyze the direct asymmetric allylic addition of N-aryl alkylidene-succinimides to imines with high enantioselectivities.…”