Yibo Xu

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.

The Reaction of Grignard Reagents with Bunte Salts: A Thiol-Free Synthesis of Sulfides

S-Alkyl, S-aryl, and S-vinyl thiosulfate sodium salts (Bunte salts) react with Grignard reagents to give sulfides in good yields. The S-alkyl Bunte salts are prepared from odorless sodium thiosulfate by an SN2 reaction with alkyl halides. A Cu-catalyzed coupling of sodium thiosulfate with aryl and vinyl halides was developed to access S-aryl and S-vinyl Bunte salts. The reaction is amenable to a broad structural array of Bunte salts and Grignard reagents. Importantly, this route to sulfides avoids the use of malodorous thiol starting materials or byproducts.

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.

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.

Efficient Asymmetric Synthesis of Structurally Diverse P-Stereogenic Phosphinamides for Catalyst Design†

The use of chiral phosphinamides is relatively unexplored because of the lack of a general method for the synthesis. Reported herein is the development of a general, efficient, and highly enantioselective method for the synthesis of structurally diverse P-stereogenic phosphinamides. The method relies on nucleophilic substitution of a chiral phosphinate derived from the versatile chiral phosphinyl transfer agent 1,3,2-benzoxazaphosphinine-2-oxide. These chiral phosphinamides were utilized for the first synthesis of readily tunable P-stereogenic Lewis base organocatalysts, which were used successfully for highly enantioselective catalysis.

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.

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.

Efficient Synthesis of a Small Molecule, Nonpeptide Inhibitor of LFA-1

A three-stage process for the synthesis of LFA-1 inhibitor 1 from amine 4 with an overall yield of 65% is described. The key stage involves a Ph(3)PCl(2)-induced dehydration/cyclization of urea 6 followed by a regioselective bromination to give 1H-imidazo[1,2-a]imidazol-2-one 9. Br/Mg exchange of 9 followed by addition to SO(2) in THF and subsequent oxidation produces a sulfonyl chloride which is directly reacted with L-alaninamide using K(2)CO(3) as base in aqueous DMF/THF to give 1 in a one-pot operation. The process was implemented for the production of 1 on a metric ton scale.

Synthesis of a salbutamol dimer

Abstract First synthesis of the diastereomeric mixture of Salbutamol dimer ( 2 ) is described. The synthesis provides access to multi-gram quantities of 2 for reference supplies and further analytical and toxicology investigations. It also confirmed the proposed structure by comparison to authentic sample.

Facile entry to an efficient and practical enantioselective synthesis of a polycyclic cholesteryl ester transfer protein inhibitor.

An efficient enantioselective synthesis of the chiral polycyclic cholesteryl ester transfer protein (CETP) inhibitor 1 has been developed. The synthesis was rendered practical for large scale via the development of a modified Hantzsch-type reaction to prepare the sterically hindered pyridine ring, enantioselective hydrogenation of hindered ketone 6 utilizing novel BIBOP-amino-pyridine derived Ru complex, efficient ICl promoted lactone formation, and a BF3 mediated hydrogenation process for diastereoselective lactol reduction. This efficient route was successfully scaled to produce multikilogram quantities of challenging CETP drug candidate 1.