Soo Bong Han

Vicinal Difunctionalization of Alkenes: Chlorotrifluoromethylation with CF3SO2Cl by Photoredox Catalysis

Photoredox-catalyzed vicinal chlorotrifluoromethylation of alkene is described. In the presence of Ru(Phen)3Cl2, CF3SO2Cl was used as a source for the CF3 radical and chloride ion under visible light irradiation. Various terminal and internal alkenes were transformed to their vicinal chlorotrifluoromethylated derivatives. Biologically active compounds were applied under the condition to obtain desired products, suggesting that the method could be feasible for late-stage modification in drug discovery.

Enantioselective allylation, crotylation, and reverse prenylation of substituted isatins: iridium-catalyzed C-C bond-forming transfer hydrogenation.

3-Substituted-3-hydroxy-oxindoles appear as substructures within a fascinating array of natural products, including the convulutamydines,[1a,b] maremycins,[1c,d] donaxaridines,[1e,f] dioxibrassinins,[1g,h,i] celogentin K,[1j] hydroxyglucoisatisins[1k] and TMC-95A–D (Figure 1).[1l] While catalytic asymmetric additions to isatins are known,[2–6] highly enantioselective catalytic allylation, crotylation and reverse prenylation of isatins has remained elusive. In the course developing hydrogen-mediated C-C couplings beyond hydroformylation,[7–15] chiral ortho-cyclometallated iridium C,O-benzoates were found to catalyze highly enantioselective carbonyl allylation,[14a,b] crotylation[14c] and reverse prenylation[12d] under transfer hydrogenation conditions. In contrast to classical allylation procedures that employ stoichiometric organometallic reagents,[16] transfer hydrogenation protocols exploit allyl acetate, α-methyl allyl acetate and 1,1-dimethylallene as precursors to transient allyl-, crotyl- and prenylmetal intermediates, respectively.[12,14a–c] To further evaluate the scope of this emergent methodology, catalytic enantioselective additions to ketones were explored.[17,18] In this account, we report that activated ketones in the form of substituted isatins are subject to highly enantioselective carbonyl allylation, crotylation and reverse prenylation, constituting a convenient synthesis of optically enriched 3-substituted-3-hydroxy-oxindoles. Figure 1 Examples of naturally occurring 3-substituted-3-hydroxy-oxindoles. Our initial studies focused on the asymmetric allylation of N-benzyl isatin 1a. Using the cyclometallated C,O-benzoate generated in situ from [Ir(cod)Cl]2, BIPHEP and 4-chloro-3-nitrobenzoic acid,[14b] the coupling of allyl acetate (1000 mol%) to 1a at 100 °C in THF (0.2 M) delivered the tertiary homoallyl alcohol 2a in 42% isolated yield. Under otherwise identical conditions, but with a lower loading of allyl acetate (200 mol%) and optimization of reaction temperature, reaction time, and concentration, the isolated yield of homoallyl alcohol 2a was increased to 77%. An assay of chelating chiral phosphine ligands was undertaken, which revealed dramatic enhancement in the level of asymmetric induction at lower reaction temperatures. However, lower temperatures also diminished conversion. This impasse was resolved by increasing the loading of isopropanol from 200 mol% to 400 mol%, which enabled conversion of N-benzyl isatin 1a to homoallyl alcohol 2a in 73% isolated yield and 91% enantiomeric excess using CTH-(R)-P-PHOS as ligand. Notably, under analogous conditions employing our initially disclosed iridium catalyst modified by 3-nitrobenzoic acid,[14a,b] 2a is obtained in 61% isolated yield and 90% enantiomeric excess. These data further illustrate how catalyst performance is enhanced through structural variation of the C,O-benzoate moiety. Data pertaining to the optimization of the catalytic enantioselective allylation of N-benzyl isatin 1a is tabulated in the supporting information. Optimal conditions identified for the conversion of N-benzyl isatin 1a to the hydroxy-oxindole 2a were applied to substituted isatins 1a–1g (Table 1). To our delight, the products of ketone allylation 2a–2g were produced in moderate to excellent isolated yield (65–92% yield) with uniformly high levels of optical enrichment (91–96% ee). The absolute stereochemical assignment of adducts 2a–2g are based upon that determined for the 5-bromo-dervative 2b via single crystal X-ray diffraction analysis using the anomalous dispersion method. Table 1 Catalytic enantioselective allylation N-benzyl isatins 1a–1g via iridium catalyzed C-C bond forming transfer hydrogenation. Given these favorable results, the crotylation of substituted isatins 1a–1g was attempted under identical conditions employing α-methyl allyl acetate as the crotyl donor (Table 2). The products of ketone crotylation 3a–3g were produced in moderate to excellent isolated yield (64–87% yield) with moderate to excellent levels of optical enrichment (80–92% ee). In general, crotylation required longer reaction times (Table 2, entries 1, 2, 5–7). Additionally, it was found that lower loadings of Cs2CO3 increased conversion in certain cases. The absolute stereochemical assignment of adducts 3a–3g are based upon that determined for the 5-bromo-dervative 3b via single crystal X-ray diffraction analysis using the anomalous dispersion method. Table 2 Catalytic enantioselective crotylation of N-benzyl isatins 1a–1g via iridium catalyzed C-C bond forming transfer hydrogenation. Finally, the reverse prenylation of substituted isatins 1a–1g was attempted (Table 3). To our delight, adducts 4a–4g were generated in uniformly high isolated yields (70–90% yield) and levels of optical enrichment (90–96 % ee) under mild conditions. Notably, this transformation enables creation of two contiguous quaternary carbon centers. The absolute stereochemical assignment of adducts 4a–4g are based upon that determined for the 5-bromo-dervative 4b via single crystal X-ray diffraction analysis using the anomalous dispersion method. Here, the enantiofacial selectivity of carbonyl addition is opposite to that observed in the case of allylation and crotylation. Table 3 Catalytic enantioselective prenylation of N-benzyl isatins 1a–1g via iridium catalyzed C-C bond forming transfer hydrogenation. The inversion in absolute stereochemistry observed in isatin reverse prenylation merits further explanation. The catalytic mechanism for carbonyl prenylation employing 1,1-dimethylallene is analogous to that previously reported for corresponding allylations and crotylations (Scheme 1, left).14b,c Assuming isatin crotylation occurs through a chair-like transition structure and an (E)-σ-crotyl iridium intermediate, previously proposed absolute stereochemical models agrees with the observed π-facial selectivity with respect to the crotyl partner.14c The latter observation suggests that isatin crotylation occurs by way of transition structure A, whereas isatin prenylation occurs by way of transition structures B. The basis of this partitioning may arise from non-bonded interactions of the axial methyl group of the σ-prenyl iridium intermediate with the amide π-bond of isatin, which is presumably more destabilizing than non-bonded interactions of the axial methyl group with the electron-deficient rim of the arene (Scheme 1, right). Scheme 1 A simplified catalytic mechanism depicting isatin prenylation via transfer hydrogenation (left) and a plausible stereochemical model accounting for the observed inversion in absolute stereochemistry in the prenylation of isatins (right).a In summary, we report the first enantioselective allylations, crotylations and prenylations of isatin, which are achieved via isopropanol-mediated transfer hydrogenation. Unlike conventional allylation methodologies that employ stoichiometric quantities of allylmetal reagents, the present method exploits allyl acetate, α-methyl allyl acetate and 1,1-dimethylallene as precursors to transient allyl-, crotyl- and prenylmetal intermediates, respetively.[12,14a–c] To our knowledge, these studies represent the first examples of catalytic enantioselective ketone allylation, crotylation and prenylation in the absence of stoichiometric allylmetal reagents. Future studies will focus on the development of related C-C bond forming transfer hydrogenations and synthetic applications of the methods reported herein.

anti-Diastereo- and Enantioselective Carbonyl Crotylation from the Alcohol or Aldehyde Oxidation Level Employing a Cyclometallated Iridium Catalyst: α-Methyl Allyl Acetate as a Surrogate to Preformed Crotylmetal Reagents

Under the conditions of transfer hydrogenation employing an ortho-cyclometallated iridium catalyst generated in situ from [Ir(cod)Cl](2), 4-cyano-3-nitrobenzoic acid and the chiral phosphine ligand (S)-SEGPHOS, alpha-methyl allyl acetate couples to alcohols 1a-1j with complete levels of branched regioselectivity to furnish products of carbonyl crotylation 3a-3j, which are formed with good levels of anti-diastereoselectivity and exceptional levels of enantioselectivity. An identical set of optically enriched carbonyl crotylation products 3a-3j is accessible from the corresponding aldehydes 2a-2j under the same conditions, but employing isopropanol as the terminal reductant. Experiments aimed at probing the origins of stereoselection establish a matched mode of ionization for the (R)-acetate and the iridium catalyst modified by (S)-SEGPHOS, as well as reversible ionization of the allylic acetate with rapid pi-facial interconversion of the resulting pi-crotyl intermediate in advance of C-C bond formation. Additionally, rapid alcohol-aldehyde redox equilibration in advance of carbonyl addition is demonstrated. Thus, anti-diastereo- and enantioselective carbonyl crotylation from the alcohol or aldehyde oxidation level is achieved in the absence of any stoichiometric metallic reagents or stoichiometric metallic byproducts.

Enantioselective Carbonyl Reverse Prenylation from the Alcohol or Aldehyde Oxidation Level Employing 1,1-Dimethylallene as the Prenyl Donor

Enantioselective transfer hydrogenation of 1,1-dimethylallene 1a in the presence of aromatic, alpha,beta-unsaturated, or aliphatic aldehydes 2a-i mediated by 2-propanol and employing a cyclometalated iridium C,O-benzoate derived from allyl acetate, m-nitrobenzoic acid, and (S)-SEGPHOS delivers reverse-prenylation products 4a-i in good to excellent isolated yields (65-96%) and enantioselectivities (87-93% ee). In the absence of 2-propanol, enantioselective carbonyl reverse prenylation is achieved directly from the alcohol oxidation level to furnish an equivalent set of adducts 4a-i in good to excellent isolated yields (68-94%) and enantioselectivities (86-91% ee). Competition and isotopic labeling experiments suggest rapid alcohol-aldehyde redox equilibration in advance of carbonyl addition along with capture of the kinetically formed pi-allyl complex at a higher rate than reversible beta-hydride elimination-hydrometalation. This protocol represents an alternative to the use of allylmetal reagents in enantioselective carbonyl reverse prenylation and represents the first use of allenes in enantioselective C-C bond-forming transfer hydrogenation.

Total Synthesis of (+)-Roxaticin via C−C Bond Forming Transfer Hydrogenation: A Departure from Stoichiometric Chiral Reagents, Auxiliaries, and Premetalated Nucleophiles in Polyketide Construction

A total synthesis of the oxo-polyene macrolide (+)-roxaticin is achieved in 20 steps from 1,3-propanediol. In this approach, 9 of 10 C-C bonds formed in the longest linear sequence are made via metal catalysis, including 7 C-C bonds formed by iridium catalyzed alcohol C-C coupling. Notably, the present synthesis, which represents the most concise preparation of any oxo-polyene macrolide reported to date, is achieved in the absence of chiral reagents and chiral auxiliaries with minimal use of premetalated C-nucleophiles.

Enantioselective iridium-catalyzed carbonyl allylation from the alcohol oxidation level via transfer hydrogenation: minimizing pre-activation for synthetic efficiency

Existing methods for enantioselective carbonyl allylation, crotylation and tert-prenylation require stoichiometric generation of pre-metallated nucleophiles, and often employ stoichiometric chiral modifiers. Under the conditions of transfer hydrogenation employing an ortho-cyclometallated iridium C,O-benzoate catalyst, enantioselective carbonyl allylations, crotylations and tert-prenylations are achieved in the absence of stoichiometric metallic reagents or stoichiometric chiral modifiers. Moreover, under transfer hydrogenation conditions, primary alcohols function dually as hydrogen donors and aldehyde precursors, enabling enantioselective carbonyl addition directly from the alcohol oxidation level.

Diastereo- and enantioselective hydrogenative aldol coupling of vinyl ketones: design of effective monodentate TADDOL-like phosphonite ligands.

We report the first enantioselective reductive aldol couplings of vinyl ketones, which were achieved through the design of a novel monodentate TADDOL-like phosphonite ligand. Specifically, hydrogenation of commercially available methyl vinyl ketone (MVK) or ethyl vinyl ketone (EVK) in the presence of aldehydes 1a-7a using cationic rhodium catalysts modified by chiral TADDOL-like phosphonite ligands AP-I and AP-IV produces aldol adducts 1b-7b and 1c-7c with excellent control of relative and absolute stereochemistry. The absolute stereochemical assignments of the aldol adducts are made in analogy to that determined for the 5-bromophthalimido derivative of aldol adduct 1b and the 2-bromo-5-nitrobenzoate of 3b, which were established by single-crystal X-ray diffraction analysis using the anomalous dispersion method.

Diastereo- and Enantioselective anti-Alkoxyallylation Employing Allylic gem-Dicarboxylates as Allyl Donors via Iridium-Catalyzed Transfer Hydrogenation

Enantioselective transfer hydrogenation of gem-dibenzoate 1e in the presence of aromatic, alpha,beta-unsaturated, or aliphatic aldehydes 2a-i mediated by isopropyl alcohol and employing a cyclometalated iridium C,O-benzoate derived from allyl acetate, 4-cyano-3-nitrobenzoic acid, and (R)-SEGPHOS delivers products of alkoxyallylation 3a-i, 4a, 4e, 4f, and 4i in good isolated yields (62-82%) with good to excellent diastereoselectivities (7:1 to 18:1 dr) and exceptional enantioselectivities (90-99% ee). This protocol provides an alternative to the use of premetalated nucleophiles in carbonyl alkoxyallylation.

Iridium Catalyzed anti-Diastereo- and Enantioselective Carbonyl (Trimethylsilyl)allylation from the Alcohol or Aldehyde Oxidation Level

Using the ortho-cyclometalated pi-allyl iridium precatalyst (R)-I derived from [Ir(cod)Cl](2), 4-cyano-3-nitrobenzoic acid, (R)-SEGPHOS, and allyl acetate, enantioselective transfer hydrogenation of alpha-(trimethylsilyl)allyl acetate in the presence of aldehydes 2a-i mediated by 2-propanol delivers products of (trimethylsilyl)allylation 4a-i in good isolated yields and with exceptional levels of anti-diastereoselectivity and enantioselectivity (90-99% ee). In the absence of 2-propanol, but under otherwise identical reaction conditions, carbonyl (trimethylsilyl)allylation is achieved directly from the alcohol oxidation level to furnish an equivalent set of adducts 4a-i with roughly equivalent isolated yields and stereoselectivities. To evaluate the synthetic utility of the reaction products 4a-i, adduct 4g was converted to the 1,4-ene-diol 5g via dioxirane-mediated oxidative desilylation with allylic transposition, the allylic alcohol 6g via protodesilylation with allylic transposition, and the gamma-lactam 7g via chlorosulfonyl isocyanate-mediated cycloaddition.

Catalyst-Directed Diastereoselectivity in Hydrogenative Couplings of Acetylene to α-Chiral Aldehydes: Formal Synthesis of All Eight l-Hexoses

Hydrogenative coupling of acetylene to alpha-chiral aldehydes 1a-4a using enantiomeric rhodium catalysts ligated by (S)-MeO-BIPHEP and (R)-MeO-BIPHEP delivers the diastereomeric products of carbonyl-(Z)-butadienylation 1b-4b and 1c-4c, respectively, with good to excellent levels of catalyst directed diastereofacial selectivity. Diastereomeric L-glyceraldehyde acetonide adducts 1b and 1c were converted to the four isomeric enoates 6b, 8b, 6c, and 8c, representing a formal synthesis of all eight L-hexoses.