TEFDDOLs (α,α,α′,α′-Tetrakis(perfluoroaryl/alkyl)-2,2′-dimethyl-1,3-dioxolane-4,5-dimethanols): Highly Fluorinated Chiral H‑Bond Donors and Brønsted Acids with Distinct H‑Bonding Patterns and Supramolecular Architectures

The synthesis of six enantiopure α,α,α′,α′-tetrakis­(perfluoroalkyl/aryl)-2,2′-dimethyl-1,3-dioxolane-4,5-dimethanols (TEFDDOLs), by addition of perfluorinated organolithium reagents or Ruppert’s reagent (TMS-CF₃) to isopropylidene tartaric dichloride, is reported. X-ray crystal structures of the TEFDDOLs alone or in complexes with H-bond acceptors such as water and DABCO revealed that this new class of highly fluorinated chiral 1,4-diols forms distinct intra- and intermolecular H-bond patterns. Intramolecular OH–OH bonding accounts for the relatively high acidity of the perfluoroalkyl TEFDDOLs (p<i>K</i>_a in DMSO: tetrakis-CF₃, 5.7; tetrakis-C₂F₅, 2.4). For the tetrakis­(perfluorophenyl) TEFDDOL, a quite unusual “pseudo-anti” conformation of the diol, with no intramolecular (and no intermolecular) OH–OH bonds, was found both in the crystal and in solution (DOSY and NOESY NMR). The latter conformation results from a total of four intramolecular OH–F_aryl hydrogen bonds overriding OH–OH bonding. Due to their H-bonding properties, the TEFDDOLs are promising new building blocks for supramolecular and potentially catalytic applications

Large-Scale Synthesis of Singh’s Catalyst in a One-Pot Procedure Starting from Proline

A practical one-pot procedure for the preparation of Singh’s catalyst from either l-/d-proline or Boc-proline is described. The coupling partner, a chiral amino alcohol, can be prepared and used directly without purification from the corresponding amino acid ester. Moreover, a procedure for <i>tert</i>-butoxycarbonyl (Boc) group removal using concentrated HCl in MeOH–DCM was developed and utilized for the multigram-scale synthesis of Singh’s catalyst

Highly Enantioselective Organocatalytic Trifluoromethyl Carbinol SynthesisA Caveat on Reaction Times and Product Isolation

Aldol reactions with trifluoroacetophenones as acceptors yield chiral α-aryl, α-trifluoromethyl tertiary alcohols, valuable intermediates in organic synthesis. Of the various organocatalysts examined, Singh’s catalyst [(2<i>S</i>)-<i>N</i>-[(1<i>S</i>)-1-hydroxydiphenylmethyl-3-methylbutyl]-2-pyrrolidinecarbox­amide] was found to efficiently promote this organocatalytic transformation in a highly enantioselective manner. Detailed reaction monitoring (¹⁹F-NMR, HPLC) showed that, up to full conversion, the catalytic transformation proceeds under kinetic control and affords up to 95% ee in a time-independent manner. At longer reaction times, the catalyst effects racemization. For the product aldols, even weak acids (such as ammonium chloride) or protic solvents, can induce racemization, too. Thus, acid-free workup, at carefully chosen reaction time, is crucial for the isolation of the aldols in high (and stable) enantiomeric purity. As evidenced by ¹⁹F-NMR, X-ray structural analysis, and independent synthesis of a stable intramolecular variant, Singh’s catalyst reversibly forms a catalytically inactive (“parasitic”) intermediate, namely a <i>N</i>,<i>O</i>-hemiacetal with trifluoroacetophenones. X-ray crystallography also allowed the determination of the product aldols’ absolute configuration (<i>S</i>)

Highly Enantioselective Organocatalytic Trifluoromethyl Carbinol SynthesisA Caveat on Reaction Times and Product Isolation

Aldol reactions with trifluoroacetophenones as acceptors yield chiral α-aryl, α-trifluoromethyl tertiary alcohols, valuable intermediates in organic synthesis. Of the various organocatalysts examined, Singh’s catalyst [(2<i>S</i>)-<i>N</i>-[(1<i>S</i>)-1-hydroxydiphenylmethyl-3-methylbutyl]-2-pyrrolidinecarbox­amide] was found to efficiently promote this organocatalytic transformation in a highly enantioselective manner. Detailed reaction monitoring (¹⁹F-NMR, HPLC) showed that, up to full conversion, the catalytic transformation proceeds under kinetic control and affords up to 95% ee in a time-independent manner. At longer reaction times, the catalyst effects racemization. For the product aldols, even weak acids (such as ammonium chloride) or protic solvents, can induce racemization, too. Thus, acid-free workup, at carefully chosen reaction time, is crucial for the isolation of the aldols in high (and stable) enantiomeric purity. As evidenced by ¹⁹F-NMR, X-ray structural analysis, and independent synthesis of a stable intramolecular variant, Singh’s catalyst reversibly forms a catalytically inactive (“parasitic”) intermediate, namely a <i>N</i>,<i>O</i>-hemiacetal with trifluoroacetophenones. X-ray crystallography also allowed the determination of the product aldols’ absolute configuration (<i>S</i>)

Highly Enantioselective Organocatalytic Trifluoromethyl Carbinol SynthesisA Caveat on Reaction Times and Product Isolation

Aldol reactions with trifluoroacetophenones as acceptors yield chiral α-aryl, α-trifluoromethyl tertiary alcohols, valuable intermediates in organic synthesis. Of the various organocatalysts examined, Singh’s catalyst [(2<i>S</i>)-<i>N</i>-[(1<i>S</i>)-1-hydroxydiphenylmethyl-3-methylbutyl]-2-pyrrolidinecarbox­amide] was found to efficiently promote this organocatalytic transformation in a highly enantioselective manner. Detailed reaction monitoring (¹⁹F-NMR, HPLC) showed that, up to full conversion, the catalytic transformation proceeds under kinetic control and affords up to 95% ee in a time-independent manner. At longer reaction times, the catalyst effects racemization. For the product aldols, even weak acids (such as ammonium chloride) or protic solvents, can induce racemization, too. Thus, acid-free workup, at carefully chosen reaction time, is crucial for the isolation of the aldols in high (and stable) enantiomeric purity. As evidenced by ¹⁹F-NMR, X-ray structural analysis, and independent synthesis of a stable intramolecular variant, Singh’s catalyst reversibly forms a catalytically inactive (“parasitic”) intermediate, namely a <i>N</i>,<i>O</i>-hemiacetal with trifluoroacetophenones. X-ray crystallography also allowed the determination of the product aldols’ absolute configuration (<i>S</i>)

Highly Enantioselective Organocatalytic Trifluoromethyl Carbinol SynthesisA Caveat on Reaction Times and Product Isolation

Aldol reactions with trifluoroacetophenones as acceptors yield chiral α-aryl, α-trifluoromethyl tertiary alcohols, valuable intermediates in organic synthesis. Of the various organocatalysts examined, Singh’s catalyst [(2<i>S</i>)-<i>N</i>-[(1<i>S</i>)-1-hydroxydiphenylmethyl-3-methylbutyl]-2-pyrrolidinecarbox­amide] was found to efficiently promote this organocatalytic transformation in a highly enantioselective manner. Detailed reaction monitoring (¹⁹F-NMR, HPLC) showed that, up to full conversion, the catalytic transformation proceeds under kinetic control and affords up to 95% ee in a time-independent manner. At longer reaction times, the catalyst effects racemization. For the product aldols, even weak acids (such as ammonium chloride) or protic solvents, can induce racemization, too. Thus, acid-free workup, at carefully chosen reaction time, is crucial for the isolation of the aldols in high (and stable) enantiomeric purity. As evidenced by ¹⁹F-NMR, X-ray structural analysis, and independent synthesis of a stable intramolecular variant, Singh’s catalyst reversibly forms a catalytically inactive (“parasitic”) intermediate, namely a <i>N</i>,<i>O</i>-hemiacetal with trifluoroacetophenones. X-ray crystallography also allowed the determination of the product aldols’ absolute configuration (<i>S</i>)

1,4-Bis-Dipp/Mes-1,2,4-Triazolylidenes: Carbene Catalysts That Efficiently Overcome Steric Hindrance in the Redox Esterification of α- and β‑Substituted α,β-Enals

As reported by Scheidt and Bode in 2005, sterically nonencumbered α,β-enals are readily converted to saturated esters in the presence of alcohols and N-heterocyclic carbene catalysts, e.g., benzimidazolylidenes or triazolylidenes. However, substituents at the α- or β-position of the α,β-enal substrate are typically not tolerated, thus severely limiting the substrate spectrum. On the basis of our earlier mechanistic studies, a set of <i>N</i>-Mes- or <i>N</i>-Dipp-substituted 1,2,4-triazolium salts were synthesized and evaluated as (pre)­catalysts in the redox esterification of various α- or β-substituted enals. In particular the 1,4-bis-Mes/Dipp-1,2,4-triazolylidenes overcome the above limitations and efficiently catalyze the redox esterification of a whole series of α/β-substituted enals hitherto not amenable to NHC-catalyzed transformations. The synthetic value of 1,4-bis-Mes/Dipp-1,2,4-triazolylidenes is further demonstrated by the one-step bicyclization of 10-oxocitral to (racemic) nepetalactone in diastereomerically pure form

Ene–Diene Transmissive Cycloaddition Reactions with Singlet Oxygen: The <i>Vinylogous Gem Effect</i> and Its Use for Polyoxyfunctionalization of Dienes

The singlet oxygen reactivities and regioselectivities of the model compounds <b>1b</b>–<b>d</b> were compared with those of the geminal (gem) selectivity model ethyl tiglate (<b>1a</b>). The kinetic cis effect is <i>k</i>_<i>E</i>/<i>k</i>_<i>Z</i> = 5.2 for the tiglate/angelate system <b>1a</b>/<b>1a′</b> without a change in the high gem regioselectivity. Further conjugation to vinyl groups enabled mode-selective processes, namely, [4 + 2] cycloadditions versus ene reactions. The site-specific effects of methylation on the mode selectivity and the regioselectivity of the ene reaction were studied for dienes <b>1e</b>–<b>g</b>. A vinylogous gem effect was observed for the γ,δ-dimethylated and α,γ,δ-trimethylated substrates <b>1h</b> and <b>1i</b>, respectively. The corresponding phenylated substrates <b>1j</b>–<b>l</b> showed similar mode selectivity, as monomethylated <b>1j</b> exhibited exclusively [4 + 2] reactivity while the tandem products <b>12</b> and <b>14</b> were isolated from the di- and trimethylated substrates <b>1k</b> and <b>1l</b>, respectively. The vinylogous gem effect favors the formation of 1,3-dienes from the substrates, and thus, secondary singlet oxygen addition was observed to give hydroperoxy-1,2-dioxenes <b>19</b> and <b>20</b> in an ene–diene transmissive cycloaddition sequence. These products were reduced to give alcohols (<b>16</b>, <b>17</b>, and <b>18</b>) or furans (<b>24</b> and <b>25</b>), respectively, or treated with titanium­(IV) alkoxides to give the epoxy alcohols <b>26</b> and <b>27</b>. The vinylogous gem effect is rationalized by DFT calculations showing that biradicals are the low-energy intermediates and that no reaction path bifurcations compete

Ene–Diene Transmissive Cycloaddition Reactions with Singlet Oxygen: The <i>Vinylogous Gem Effect</i> and Its Use for Polyoxyfunctionalization of Dienes

The singlet oxygen reactivities and regioselectivities of the model compounds <b>1b</b>–<b>d</b> were compared with those of the geminal (gem) selectivity model ethyl tiglate (<b>1a</b>). The kinetic cis effect is <i>k</i>_<i>E</i>/<i>k</i>_<i>Z</i> = 5.2 for the tiglate/angelate system <b>1a</b>/<b>1a′</b> without a change in the high gem regioselectivity. Further conjugation to vinyl groups enabled mode-selective processes, namely, [4 + 2] cycloadditions versus ene reactions. The site-specific effects of methylation on the mode selectivity and the regioselectivity of the ene reaction were studied for dienes <b>1e</b>–<b>g</b>. A vinylogous gem effect was observed for the γ,δ-dimethylated and α,γ,δ-trimethylated substrates <b>1h</b> and <b>1i</b>, respectively. The corresponding phenylated substrates <b>1j</b>–<b>l</b> showed similar mode selectivity, as monomethylated <b>1j</b> exhibited exclusively [4 + 2] reactivity while the tandem products <b>12</b> and <b>14</b> were isolated from the di- and trimethylated substrates <b>1k</b> and <b>1l</b>, respectively. The vinylogous gem effect favors the formation of 1,3-dienes from the substrates, and thus, secondary singlet oxygen addition was observed to give hydroperoxy-1,2-dioxenes <b>19</b> and <b>20</b> in an ene–diene transmissive cycloaddition sequence. These products were reduced to give alcohols (<b>16</b>, <b>17</b>, and <b>18</b>) or furans (<b>24</b> and <b>25</b>), respectively, or treated with titanium­(IV) alkoxides to give the epoxy alcohols <b>26</b> and <b>27</b>. The vinylogous gem effect is rationalized by DFT calculations showing that biradicals are the low-energy intermediates and that no reaction path bifurcations compete