Depeng Zhao

Highly Enantioselective 1,4-Addition of Diethyl Phosphite to Enones Using a Dinuclear Zn Catalyst

Zinc benefits: The first catalytic asymmetric phospha-Michael addition of enones has been developed. Under mild reaction conditions, the gamma-oxo phosphonates could be obtained in high yields (up to 99%) with excellent enantioselectivities (93-99% ee; see scheme). The strategy makes the asymmetric synthesis of biologically important phosphonate compounds more accessible.

Highly Enantioselective Conjugate Additions of Phosphites to α,β‐Unsaturated N‐Acylpyrroles and Imines: A Practical Approach to Enantiomerically Enriched Amino Phosphonates

The first highly enantioselective phosphonylation of alpha,beta-unsaturated N-acylpyrroles has been developed. Excellent yields (91-99 %) and enantioselectivities (up to >99 % enantiomeric excess (ee)) were observed for a broad spectrum of both phosphites and N-acylpyrroles under mild conditions. In particular, when diethyl phosphite was employed to test the scope of the N-acylpyrroles, almost optically pure products (98 to >99 % ee) were obtained for 20 examples of N-acylpyrroles. Moreover, optically pure alpha-substituted beta- or gamma-amino phosphonates can be obtained by several simple transformations of the pyrrolyl phosphonates. The versatility of the N-acylpyrrole moiety makes the phosphorus adducts powerful chiral building blocks that enable the synthesis of various phosphonate-containing compounds. Finally, the present strategy can also be applied to the asymmetric hydrophosphonylation of N-acylimines with high enantioselectivities (93 to >99 % ee).

Zinc-mediated asymmetric additions of dialkylphosphine oxides to α,β-unsaturated ketones and N-sulfinylimines.

A catalyst was synthesized on the basis of Trosts dinuclear catalyst characterized by working well without pyridine in the present phospha-Michael reaction. Nevertheless, the presence of pyridine is still advantageous in the present system. The substrate scope was successfully extended to enones employing diallyl phosphine oxide as a nucleophile. Excellent yields and enantioselectivities (up to >99% ee) were achieved for a wide scope of enones employing the catalyst under mild conditions. The detailed reaction mechanism is also discussed herein. Finally, the unprecedented asymmetric additions of dialkylphosphine oxides to N-sulfinylimines were achieved by using Et(2)Zn as a base.

Catalytic Asymmetric Hydrophosphinylation of α,β-Unsaturated N-Acylpyrroles: Application of Dialkyl Phosphine Oxides in Enantioselective Synthesis of Chiral Phosphine Oxides or Phosphines

Dialkyl phosphine oxides were introduced in catalytic asymmetric transformations for the first time. An unprecedented phospha-Michael reaction of dialkyl phosphine oxide with alpha,beta-unsaturated N-acylpyrroles was disclosed. Excellent enantioselectivities (94-->99% ee) and chemical yields (up to 99%) were achieved with a broad substrate scope of the N-acylpyrroles. Importantly, pyridine was found to be critical to achieve good results for the present reaction.

Highly Diastereo- and Enantioselective Synthesis of α-Alkyl Norstatine Derivatives: Catalytic Asymmetric Mannich Reactions of 5H-Oxazol-4-ones†

The catalytic asymmetric synthesis of b-amino acids has been an intense area of research in recent years as these unnatural amino acids are basic elements of peptides and peptidomimetic precursors of many physiologically active compounds. In particular, many efforts have focused on synthetic methods towards a-hydroxy b-amino acid (norstatine) derivatives, which have been used as a side chain in taxol analogues, and are observed in natural products such as leuhistin. Despite previous success, the stereoselective synthesis of a-alkyl a-hydroxy b-amino acids bearing a quaternary stereogenic center is still challenging. In 2010, Wolfe and co-workers described an asymmetric tandem Wittig rearrangement/Mannich reaction to prepare such compounds using 2-phenylcyclohexanol as a chiral auxiliary (Scheme 1a). With this protocol, both synand anti-selective products were accessed with high enantioselectivities and diastereoselectivities using specific protective groups. To date, only a few catalytic methods have been developed for a-alkyl norstatine derivatives. Hu, Gong, and co-workers reported a three-component reaction of diazo compounds with alcohols and imines catalyzed by [Rh2(OAc)4] and a chiral Brønsted acid (Scheme 1 b). In this process, anti-a-aryl norstatine derivatives were synthesized in high yields with excellent enantioselectivities. In view of previous failures of the direct Mannich reaction of a-alkyl ahydroxy acids derivatives, we envisioned that the 5Hoxazol-4-ones 2 might serve as highly reactive equivalents of a-alkyl a-hydroxy acids and undergo an asymmetric Mannich reaction, an efficient approach to these compounds (Scheme 1c). The high reactivity of 5H-oxazol-4-one compared to other equivalents of a-alkyl a-hydroxy acids is attributed to the aromatization resulting from the enolization of 5H-oxazol-4-one, thus enabling the intermediates to be more stable and thereby increasing the reactivity. Herein we describe our efforts on this subject, and the resulting access to a series of syn-a-alkyl norstatine derivatives with high enantioselectivities and diastereoselectivities. Given our continued interest in the asymmetric synthesis of unnatural amino acids, especially oxazolones, 13] we decided to investigate the asymmetric Mannich reaction of the 5H-oxazol-4-ones 2. Fortunately, we found that the reaction between the N-Dpp (Dpp = diphenylphosphinoyl) imine 1 a and 5H-oxazol-4-one 2a could be efficiently catalyzed by a zinc catalyst such as the salen 4/Zn complex (Scheme 2). The Mannich adducts can be obtained with good yield and excellent diastereoselectivity, though with low enantioselectivity in the presence of salen 4/Zn (78 %, 7% ee, 20:1 d.r.) at room temperature. Encouraged by these results, a series of salen-type ligands, 5–7, were synthesized including the dinuclear zinc ligand 7. These salen/Zn catalysts were also found to be ineffective for the current Mannich reaction. In addition, the substituted binol 8 was tested and resulted in low conversion. Interestingly, when the thienylProPhenol ligand L1 was employed for the reaction, an encouraging ee value was obtained along with excellent diastereoselectivity. In contrast, the phenyl ligand L2 gave low diastereoselectivity under the same reaction conditions. With these results in hand, we then tried to optimize the Mannich reaction with L1/Et2Zn by changing variables such as reaction temperature and solvent. In running the reaction at lower temperatures, we were satisfied to find that the ee value increased to 50% at 0 8C and 67 % at 20 8C with Scheme 1. Protocols for asymmetric synthesis of a-alkyl a-hydroxy bamino acids.

Copper/DIPEA-Catalyzed, Aldehyde-Induced Tandem Decarboxylation–Coupling of Natural α-Amino Acids and Phosphites or Secondary Phosphine Oxides

A copper/DIPEA-catalyzed, aldehyde-induced intermolecular decarboxylative coupling reaction of natural α-amino acids and phosphites or secondary phosphine oxides was developed. In this process, a series of potentially useful ligands for organic synthesis and biologically important unnatural amino acid derivatives (tertiary amino phosphorus compounds) were obtained.

Direct Site-Specific and Highly Enantioselective γ-Functionalization of Linear α,β-Unsaturated Ketones: Bifunctional Catalytic Strategy†

the National Natural Science Foundation of China (nos. 91213302;20932003;21272102);the Key National S&T Program “Major New Drug Development” of the Ministry of Science and Technology (2012ZX09504001-003)

Highly Enantioselective Ring-Opening Reactions of Aziridines with Indole and Its Application in the Building of C3-Halogenated Pyrroloindolines

A magnesium-catalyzed asymmetric ring-opening reaction of aziridine with indole has been realized by employing commercially available chiral ligands. Both of the enantiomers of the ring-opening product could be obtained with good yields and a high level of enantioselectivity. The corresponding ring-opening product could be further transformed to various types of enantioenriched C3 -halogenated-pyrroloindolines.

Development of Metal/Organo Catalytic Systems for Direct Vinylogous Michael Reactions to Build Chiral γ,γ‐Disubstituted Butenolides

Cooperative catalysis is emerging as a valuable tool in asymmetric synthesis, fuelled by the identification of more efficient catalytic systems with increased substrate scopes. Many endeavors have been devoted during the past few years toward developing the right catalyst pairs giving rise to powerful bifunctional systems, and many types of organic catalysts have been used in combination with appropriate metals to achieve unprecedented enantioselective processes. In this field of research, cinchona-derived scaffolds have been recognized as one of the privileged structures for construction of new metal/organo binary catalytic systems, given their extraordinary ability to induce stereocontrol and their commercial availability. Since Mukaiyama and coworkers developed the first example of combining cinchonine with Sn ACHTUNGTRENNUNG(OTf)2 and applied it to the cyanation of aliphatic aldehydes, several combinatorial catalytic strategies concerning cinchona alkaloid derivatives have been identified that promote addition reactions through dual activation of both substrates in nucleophilic–electrophilic additions. These well-documented pioneering studies highlight the potential of this new research area and have brought us inspiration. Given these outstanding ideas and considering our continuous endeavors for designing metal/organo cooperative catalytic systems, we believe that the design and operation of such systems with a high efficiency in promoting still challenging reactions plays a pivotal role in the discovery of useful synthetic pathways. Herein, we have tried to engage a series of Lewis acids to work together with the cinchona alkaloid and have developed two effective cooperative Brønsted base/Lewis acid catalytic systems that allow easy access to chiral g,g-disubstituted butenolides from gmonosubstituted butenolides. In recent years, the generation of optically active butenolides has attracted considerable attention owing to their synthetic significance in natural products and medicinally important agents. In terms of atom economy and efficiency, tremendous excellent approaches have been accomplished toward developing direct stereocontrolled g-functionalization of furanones and g-butyrolactams to build the desired g-monosubstituted adducts. Despite these impressive contributions, however, the further use of such g-monosubstituted butenolides to be rendered direct asymmetric transformations to g,g-disubstituted butenolides is still a dark side in this area of research. The first breakthrough in the direct enantioselective preparation of g,g-disubstituted butenolides derivatives was reported by Chen and co-workers in 2010 with further contributions by the groups of Alexakis, Feng, and Mukherjee. Very recently, a highly enantioand diastereoselective asymmetric addition reaction between g-substituted butenolides and electron-deficient olefins containing an oxazolidinone moiety has been reported by Huang, Tan, and Jiang et al. during the preparation of our manuscript. In their work, the use of a tert-leucine-derived amine–thioACHTUNGTRENNUNGurea catalyst could promote either g-arylor alkyl-substituted butenolides as nucleophiles. Nevertheless, the direct asymmetric vinylogous conjugate addition of g-substituted bu ACHTUNGTRENNUNGten ACHTUNGTRENNUNGolides to the model substrate, such as enones, still represents a long-standing challenge. Moreover there is still a general deficiency of catalytic methods that tolerate variations of both the g-aryland alkyl-substituted butenolides. Herein, we disclose our own solution to these problems by exploiting complementary activation modes of binary hybrid catalytic systems, which enabled a highly direct enantioselective vinylogous addition of both the g-aryland alkyl-substituted butenolides to a series of aromatic and aliphatic enones. To establish the method we investigated the addition of gphenyl-substituted butenolide 1 a with enone 2 a in detail. The initial trail under the catalysis of quinine (B1) failed to bring about bond formation after 24 h of stirring at room temperature (Table 1, entry 1). When the reaction was performed at 60 8C, the conversion improved a little and the product was obtained in 14 % yield with 72 % ee (ee= enantiomeric excess, entry 2). We hypothesized that the poor catalytic efficiency may be due to inefficient activation of the [a] D. Yang, L. Wang, Dr. D. Zhao, F. Han, Dr. B. Zhang, Prof. Dr. R. Wang Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology School of Life Sciences and State Key Laboratory of Applied Organic Chemistry Lanzhou University, Lanzhou, 730000 (P.R. China) [b] Prof. Dr. R. Wang State Key Laboratory of Chiroscience Department of Applied Biology and Chemical Technology The Hong Kong Polytechnic University, Kowloon (Hong Kong) E-mail : wangrui@lzu.edu.cn bcrwang@polyu.edu.hk Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201204466.

A new class of highly potent and selective endomorphin-1 analogues containing α-methylene-β-aminopropanoic acids (map).

A new class of endomorphin-1 (EM-1) analogues were synthesized by introduction of novel unnatural α-methylene-β-amino acids (Map) at position 3 or/and position 4. Their binding and functional activity, metabolic stability, and antinociceptive activity were determined and compared. Most of these analogues showed high affinities for the μ-opioid receptor and an increased stability in mouse brain homogenates compared with EM-1. Examination of cAMP accumulation and ERK1/2 phosphorylation in HEK293 cells confirmed the agonist properties of these analogues. Among these new analogues, H-Tyr-Pro-Trp-(2-furyl)Map-NH(2) (analogue 12) exhibited the highest binding potency (K(i)(μ) = 0.221 nM) and efficacy (EC(50) = 0.0334 nM, E(max) = 97.14%). This analogue also displayed enhanced antinociceptive activity in vivo in comparison to EM-1. Molecular modeling approaches were then carried out to demonstrate the interaction pattern of these analogues with the opioid receptors. We found that, compared to EM-1, the incorporation of our synthesized Map at position 4 would bring the analogue to a closer binding mode with the μ-opioid receptor.