Bruce Z. Lu

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 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.

A general copper-BINAP-catalyzed asymmetric propargylation of ketones with propargyl boronates.

An operationally simple copper-BINAP-catalyzed, highly enantioselective propargylation of ketones is presented. The methodology was developed as an enantioselective process for methyl ethyl ketone and shown to be applicable to a wide variety of prochiral ketones. The resulting homopropargyl adducts are versatile latent carbonyls from which γ-butyrolactones, β-hydroxy methyl ketones, and β-hydroxycarboxylates are readily obtained.

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.

Carbamoyl anion addition to N-sulfinyl imines: highly diastereoselective synthesis of α-amino amides.

Carbamoyl anions, generated from N,N-disubstituted formamides and lithium diisopropylamide, add with high diastereoselectivity to chiral N-sulfinyl aldimines and ketimines to provide α-amino amides. The methodology enables the direct introduction of a carbonyl group without the requirement of unmasking steps as with other nucleophiles. The products may be converted to α-amino esters or 1,2-diamines. Iterative application of the reaction enabled the stereoselective synthesis of a dipeptide. Spectroscopic and computational studies support an anion structure with η(2) coordination of lithium by the carbonyl group.

Mild and General Zinc-Alkoxide-Catalyzed Allylations of Ketones with Allyl Pinacol Boronates

A general and efficient zinc-alkoxide-catalyzed allylation of a diverse array of ketones with allyl boronates is presented. The methodology is effective with 2 mol % of catalyst and with relatively short reaction times. Studies of the key exchange process are presented, which support a cyclic transition state for the boron to zinc exchange.

Diastereoselective Synthesis of α-Quaternary Aziridine-2-carboxylates via Aza-Corey–Chaykovsky Aziridination of N-tert-Butanesulfinyl Ketimino Esters

A general, scalable, and highly diastereoselective aziridination of N-tert-butanesulfinyl ketimino esters is described. The methodology has been utilized to provide straightforward access to previously unobtainable, biologically relevant α-quaternary amino esters and derivatives starting from readily available precursors.

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.