Hari P. R. Mangunuru

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.

SYNTHESIS OF PEPTOID-BASED SMALL MOLECULAR GELATORS FROM MULTIPLE COMPONENT REACTIONS

We report the synthesis and self-assembling properties of a new class of tripeptoids synthesized by a one-pot Ugi reaction from simple starting materials. Among the focused library of tripeptoids synthesized, several efficient low molecular weight gelators were obtained for aqueous DMSO and ethanol mixtures.

Preparation and Self-Assembly Study of Amphiphilic and Bispolar Diacetylene-Containing Glycolipids

Diacetylene-containing glycolipids are a unique class of compounds that are able to self-assemble and form ordered supramolecular structures. Polymerizable diacetylene glycolipids that can function as low molecular weight gelators are particularly interesting molecules which can lead to stimuli-responsive smart materials. To discover efficient organogelators with built-in functionality that may be useful in sensing local environmental changes, we have synthesized a series of novel diacetylene-containing amide and urea derivatives using D-glucosamine as the starting material. Both amphiphilic and dipolar glycolipids were synthesized, and these compounds are effective gelators for several organic solvents and aqueous solutions. The resulting gels can be cross-linked under 6 W UV light to produce blue or purple polydiacetylene gels. The cross-linked gels obtained from urea derivatives are generally dark blue and exhibit blue to red color transitions upon heating. Compared to the urea derivatives, the analogous diacetylene amides produced blue to deep purple polymerized gels, depending on the structures of the gelators. The morphologies of the gels were characterized by optical microscopy and scanning electron microscopy. Typically, self-assembled fibrous networks were observed. The synthesis and characterization of these polymerizable gelators and their UV-vis absorption upon polymerization are reported.

Synthesis and characterization of pH responsive D-glucosamine based molecular gelators

Summary Small molecular gelators are a class of compounds with potential applications for soft biomaterials. Low molecular weight hydrogelators are especially useful for exploring biomedical applications. Previously, we found that 4,6-O-benzylidene acetal protected D-glucose and D-glucosamine are well-suited as building blocks for the construction of low molecular weight gelators. To better understand the scope of D-glucosamine derivatives as gelators, we synthesized and screened a novel class of N-acetylglucosamine derivatives with a p-methoxybenzylidene acetal protective group. This modification did not exert a negative influence on the gelation. On the contrary, it actually enhanced the gelation tendency for many derivatives. The introduction of the additional methoxy group on the phenyl ring led to low molecular weight gelators with a higher pH responsiveness. The resulting gels were stable at neutral pH values but degraded in an acidic environment. The release profiles of naproxen from the pH responsive gels were also analyzed under acidic and neutral conditions. Our findings are useful for the design of novel triggered release self-assembling systems and can provide an insight into the influence of the the structure on gelation.

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.

BABIPhos Family of Biaryl Dihydrobenzooxaphosphole Ligands for Asymmetric Hydrogenation

Novel bidentate phosphine ligands BABIPhos featuring a biaryl bis-dihydrobenzooxaphosphole core are presented. Their synthesis was achieved via Pd-catalyzed reductive homocoupling of dihydrobenzooxaphosphole aryl triflates. An efficient route toward various analogues was also established, giving access to phosphines with different electronic and steric properties. The newly obtained ligands demonstrated high efficiency and selectivity in Rh-catalyzed asymmetric hydrogenation of di- and trisubstituted enamides. This new class of ligands is complementary to previously described bidentate benzooxaphosphole ligands BIBOP.

Enantioselective Synthesis of α-(Hetero)aryl Piperidines through Asymmetric Hydrogenation of Pyridinium Salts and Its Mechanistic Insights

Enantioselective synthesis of α-aryl and α-heteroaryl piperidines is reported. The key step is an iridium-catalyzed asymmetric hydrogenation of substituted N-benzylpyridinium salts. High levels of enantioselectivity up to 99.3:0.7 er were obtained for a range of α-heteroaryl piperidines. DFT calculations support an outersphere dissociative mechanism for the pyridinium reduction. Notably, initial protonation of the final enamine intermediate determines the stereochemical outcome of the transformation rather than hydride reduction of the resultant iminium intermediate.

Synthesis and characterization of amide linked triazolyl glycolipids as molecular hydrogelators and organogelators

Carbohydrate based small molecular gelators are important classes of compounds which can form useful soft materials with many practical applications. Although many different types of effective gelators have been reported, the rational design of a molecular hydrogelator is still challenging. In this research, we combined the structural features of two classes of monosaccharide based molecular gelators and obtained a new class of glycolipids that can function as molecular gelators. These new compounds were synthesized by introducing a triazole functional group to a protected 2-glucosamine through Cu(I) catalyzed azide/alkyne cycloaddition reaction (CuAAC). A series of eighteen new glycolipids containing 4,6-O-benzylidene acetal protected D-glucosamide and triazole were synthesized and characterized. The self-assembling properties of these compounds were screened in several organic solvents, aqueous solutions, and water. All eighteen compounds are effective molecular gelators for at least one solvent and, more significantly, eleven compounds are hydrogelators with minimum gelation concentrations of 0.15–1.0 wt%. The hydrogels are suitable carriers for sustained release of chloramphenicol, and for the entrapment of toluidine blue dye. These results indicate that the D-glucosamide triazoles are effective templates for small molecular hydrogelators and are useful in designing sugar based soft materials.

High-yielding continuous-flow synthesis of antimalarial drug hydroxychloroquine

Numerous synthetic methods for the continuous preparation of fine chemicals and active pharmaceutical ingredients (API’s) have been reported in recent years resulting in a dramatic improvement in process efficiencies. Herein we report a highly efficient continuous synthesis of the antimalarial drug hydroxychloroquine (HCQ). Key improvements in the new process include the elimination of protecting groups with an overall yield improvement of 52% over the current commercial process. The continuous process employs a combination of packed bed reactors with continuous stirred tank reactors for the direct conversion of the starting materials to the product. This high-yielding, multigram-scale continuous synthesis provides an opportunity to achieve increase global access to hydroxychloroquine for treatment of malaria.

Computationally Assisted Mechanistic Investigation and Development of Pd-Catalyzed Asymmetric Suzuki–Miyaura and Negishi Cross-Coupling Reactions for Tetra-ortho-Substituted Biaryl Synthesis

Metal-catalyzed cross-coupling reactions are extensively employed in both academia and industry for the synthesis of biaryl derivatives for applications to both medicine and material science. Application of these methods to prepare tetra-ortho-substituted biaryls leads to chiral atropisomeric products that introduces the opportunity to use catalyst-control to develop asymmetric cross-coupling procedures to access these important compounds. Asymmetric Pd-catalyzed Suzuki-Miyaura and Negishi cross-coupling reactions to form tetra-ortho-substituted biaryls were studied employing a collection of P-chiral dihydrobenzooxaphosphole (BOP) and dihydrobenzoazaphosphole (BAP) ligands. Enantioselectivities of up to 95:5 and 85:15 er were identified for the Suzuki-Miyaura and Negishi cross-coupling reactions, respectively. Unique ligands for the Suzuki-Miyaura reaction vs the Negishi reaction were identified. A computational study on these Suzuki-Miyaura and Negishi cross-coupling reactions enabled an understanding in the differences between the enantiodiscriminating events between these two cross-coupling reactions. These results support that enantioselectivity in the Negishi reaction results from the reductive elimination step, whereas all steps in the Suzuki-Miyaura catalytic cycle contribute to the overall enantioselection with transmetalation and reductive elimination providing the most contribution to the observed selectivities.