Yongda Zhang

Efficient Chiral Monophosphorus Ligands for Asymmetric Suzuki–Miyaura Coupling Reactions

A series of novel P-chiral monophosphorus ligands exhibit efficiency in asymmetric Suzuki-Miyaura coupling reactions, enabling the construction of an array of chiral biaryl products in high yields and excellent enantioselectivities (up to 96% ee) under mild conditions. The carbonyl-benzooxazolidinone moiety in these chiral biaryl products allows facile derivatization for further synthetic applications. A computational study has revealed that a π-π interaction between the two coupling partners can enhance the enantioselectivity of the coupling reaction.

Efficient Monophosphorus Ligands for Palladium-Catalyzed Miyaura Borylation

In combination with the Bedford Pd precursor, the new biaryl monophosphorus ligand 5 was efficient for palladium-catalyzed Miyaura borylation of sterically hindered aryl bromides at low catalyst loadings.

Efficient asymmetric synthesis of P-chiral phosphine oxides via properly designed and activated benzoxazaphosphinine-2-oxide agents.

A general, efficient, and highly diastereoselective method for the synthesis of structurally and sterically diverse P-chiral phosphine oxides was developed. The method relies on sequential nucleophilic substitution on the versatile chiral phosphinyl transfer agent 1,3,2-benzoxazaphosphinine-2-oxide, which features enhanced and differentiated P-N and P-O bond reactivity toward nucleophiles. The reactivities of both bonds are fine-tuned to allow cleavage to occur even with sterically hindered nucleophiles under mild conditions.

One-pot and regiospecific synthesis of 2,3-disubstituted indoles from 2-bromoanilides via consecutive palladium-catalyzed Sonogashira coupling, amidopalladation, and reductive elimination.

A practical one-pot and regiospecific three-component process for the synthesis of 2,3-disubstituted indoles from 2-bromoanilides was developed via consecutive palladium-catalyzed Sonogashira coupling, amidopalladation, and reductive elimination.

Direct Titanium‐Mediated Conversion of Ketones into Enamides with Ammonia and Acetic Anhydride

N-Acyl enamides are useful compounds in organic synthesis. In the realm of catalytic asymmetric hydrogenation, they are among the most exhaustively studied class of substrates, and provide access to valuable chiral amine building blocks. These substrates have also demonstrated broad utility in catalytic asymmetric C C bond forming processes such as aza–ene, Michael, Friedel–Crafts, cycloaddition, and arylation reactions. Despite the extensive applications of Nacyl enamides, their preparation remains challenging. The direct condensation of acetamide with ketones, while attractive in its simplicity, proceeds either in low yields or not at all for the majority of ketone substrates. The Pd-catalyzed cross-coupling of vinyl electrophiles with amides and the Heck reaction of N-vinylacetamide with aryl halides often require additional steps for preparation of coupling precursors and employ a costly transition metal catalyst. The addition of alkyl magnesium or alkyl lithium reagents to nitriles followed by trapping with Ac2O or AcCl has limited functional-group tolerance and requires low reaction temperatures. By far the most commonly employed procedure is the two-step conversion of ketones through ketoximes (Scheme 1). This reaction was first described in 1975 by Barton and coworkers. After a first step of oxime formation, the ketoxime was then treated with Ac2O and either pyridine at reflux, Cr(OAc)2, or Ti(OAc)3 for reductive acylation. [13] Subsequently, numerous alternative reducing agents were developed. The most commonly employed reductant is Fe powder, which was first demonstrated by Barton and Zard in 1985 and subsequently developed by Burk and Zhang in 1998. From a large scale perspective, the use of highenergy hydroxylamine, generating a high-energy oxime intermediate, and reducing the oxime at high temperatures present safety concerns. In addition, the workup of the Fe process is often tedious, requiring filtration of large amounts of inorganic salts. While several alternatives to Fe metal have emerged recently, these still rely on the same overall two-step process through a ketoxime. Our own requirements for large-scale synthesis of N-acetyl enamides for asymmetric hydrogenation prompted us to develop a more direct and process-friendly alternative in which hydroxylamine is replaced with ammonia. Herein we describe a direct, redoxfree synthesis of enamides from ketones, ammonia, and Ac2O mediated by Ti(OiPr)4. In addition, we introduce the use of edte (N,N,N’,N’-tetrakis(2-hydroxyethyl)ethylenediamine) to effect water solubilization of the Ti and allow a simple extractive workup. Our strategy for enamide synthesis was based on condensation of a ketone with ammonia to give an N-unsubstituted imine or enamine, followed by N-acetylation on addition of Ac2O. The imine formation presented a challenge due to the volatility of ammonia, which excluded the common method for imine formation by azeotropic distillation for removal of water. Therefore the condensation with NH3 at room temperature in the presence of various dehydrating agents was explored. Acetophenone 1 was treated with a dehydrating agent (2 equiv) and an ammonia source at room temperature for 24 h, followed by quenching with Et3N and Ac2O (Table 1). Little or no enamide 2 was observed with conventional desiccants and ammonia (entries 1–4). The use of sodium tetraborate (Na2B4O7) or boric anhydride (B2O3) in THF or NMP gave modest conversion to product (entries 5– 7). This prompted screening of other boron reagents, and the discovery that certain trialkyl borates, in combination with NH4Br/Et3N as the ammonia source, gave moderate conversions to product. The most effective boron reagent was 2isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (entry 11), which gave a 59 % conversion to 2. The best results were obtained by using titanium alkoxides, however, with Scheme 1. Conventional two-step enamide synthesis and the direct Timediated method.

Synthesis of 8-Arylquinolines via One-Pot Pd-Catalyzed Borylation of Quinoline-8-yl Halides and Subsequent Suzuki–Miyaura Coupling

A one-pot process has been developed for the synthesis of 8-arylquinolines via Pd-catalyzed borylation of quinoline-8-yl halides and subsequent Suzuki-Miyaura coupling with aryl halides using n-BuPAd(2) as ligand. Yields of up to 98% were obtained.

Concise and Practical Asymmetric Synthesis of a Challenging Atropisomeric HIV Integrase Inhibitor

A practical and efficient synthesis of a complex chiral atropisomeric HIV integrase inhibitor has been accomplished. The combination of a copper-catalyzed acylation along with the implementation of the BI-DIME ligands for a ligand-controlled Suzuki cross-coupling and an unprecedented bis(trifluoromethane)sulfonamide-catalyzed tert-butylation renders the synthesis of this complex molecule robust, safe, and economical. Furthermore, the overall synthesis was conducted in an asymmetric and diastereoselective fashion with respect to the imbedded atropisomer.

Enantioselective Synthesis of Diverse Sulfinamides and Sulfinylferrocenes from Phenylglycine-Derived Chiral Sulfinyl Transfer Agent

A new chiral sulfinyl transfer auxiliary derived from readily available phenylglycine was developed. This auxiliary is utilized to synthesize a diverse array of alkyl- and arylsulfinamides and sulfinylferrocenes in high yields and excellent ees. The desired products are produced in a one-pot sequence from the oxathiazolidine 2-oxide by two sequential nucleophilic additions that proceed in a stereospecific manner.

Development of a concise, scalable synthesis of a CCR1 antagonist utilizing a continuous flow Curtius rearrangement

A convergent, robust, and concise synthesis of a developmental CCR1 antagonist is described using continuous flow technology. In the first approach, following an expeditious SNAr sequence for cyclopropane introduction, a safe, continuous flow Curtius rearrangement was developed for the synthesis of a p-methoxybenzyl (PMB) carbamate. Based on kinetic studies, a highly efficient and green process comprising three chemical transformations (azide formation, rearrangement, and isocyanate trapping) was developed with a relatively short residence time and high material throughput (0.8 kg h−1, complete E-factor = ∼9) and was successfully executed on 40 kg scale. Moreover, mechanistic studies enabled the execution of a semi-continuous, tandem Curtius rearrangement and acid–isocyanate coupling to directly afford the final drug candidate in a single, protecting group-free operation. The resulting API synthesis is further determined to be extremely green (RPG = 166%) relative to the industrial average for molecules of similar complexity.

Design and Synthesis of Chiral Oxathiozinone Scaffolds: Efficient Synthesis of Hindered Enantiopure Sulfinamides and Sulfinyl Ketimines

Chiral-sulfinamide-mediated (1; see Scheme 1) chemistry has become one of the most employed approaches for the synthesis of compounds containing chiral amine functionalities. Moreover, their utility has been extended to being used as chiral ligands for many catalytic asymmetric transformations. Although the potential of chiral sulfinamides has long been recognized, only a few methods have been developed for their synthesis. Among the prominent works are the method reported by Davis et al. for the synthesis of p-toluenesulfinamide (pTSA) from Anderson s reagent, the method reported by Ellman and co-workers for the synthesis of tert-butanesulfinamide (tBSA) from tert-butyl tert-butanethiosulfinate, and others. However, these methods cannot meet the demand for accessing sulfinamides with diverse structures, which are required to fine-tune stereoselectivities in asymmetric synthesis. To meet this need, soon after the report from the group of Ellman, we designed and developed a versatile cyclic-oxathiozolidinone-based chiral sulfinyltransfer agents which provide access to a range of sulfinamides with diverse structures (Scheme 1). The success of this method hinged on the recognition that the reactivity of the cyclic oxathiozolidinone 2 could be activated by an electron-withdrawing substituent on the nitrogen atom (3), thus allowing for the facile cleavage of the S N bond to provide the desired sulfinate intermediate 4. However the reaction conditions required for the cleavage of the S O bond in 4 to liberate the desired sulfinamides relied heavily on the steric bulk of the R substituent. While the S O bond could be readily cleaved with LHMDS at 0 8C to room temperature to generate some sulfinamides, in the case of hindered substrates [e.g. R = tBu or triisopropylphenyl (TIPP)], the use of excess NH2Li/NH3 (Li/NH3) was required to incorporate the amino group. Currently, NH2Li/NH3 is prepared in situ by portionwise addition of a large excess of solid Li metal to anhydrous NH3 at reaction temperatures of less than 70 8C. These reaction conditions, in addition to the safe handling and disposal of waste generated by using NH2Li/NH3, have limited our ability to produce these important sulfinamides on large scale. Therefore, the efficient and practical synthesis of sterically hindered sulfinamides remained an unsolved problem in the field. Considering that the steric environment provided by the bulky alkyl (e.g. tBu) or aryl (e.g. TIPP) substituents of the sulfinamides is critical for obtaining high stereoselectivities, 7] it was highly desirable to develop a more practical and cost-effective process for their synthesis by replacing NH2Li/ Scheme 1. Approaches for the synthesis of sulfinamides. Ts = 4toluenesulfonamide.