Patrick Brady

Rapid and Stereochemically Flexible Synthesis of Polypropionates: Super-Silyl-Governed Aldol Cascades†

The polypropionate motif is an important structural unit present in polyketide natural products, many of which are of great interest due to their wide range of biological activities.[1] For instance, members of the erythromycin and rifamycin families have long been used as commercial antibiotics.[2] The importance of these pharmaceutical agents, as well as the potential to discover new biologically active polypropionates, makes their efficient, stereoselective chemical synthesis an important ongoing challenge. The polypropionate structure is recognized by its characteristic carbon chain decorated with alternating methyl- and hydroxyl- groups. The numerous stereogenic centers allows for many possible stereochemical permutations. Even in the case of a simple dipropionate bearing four stereogenic centers, up to 16 diastereomers are possible. This structural complexity has inspired numerous methods for stereoselective synthesis.[3] Of these methods, the aldol reaction is perhaps the most well studied and widely used in the synthesis of polypropionate natural products.[4] Other methods include crotylation,[5,6] epoxide opening,[7] [2+2] cycloaddition,[8] borylative aldehyde-diene coupling[9] and reductive aldol addition.[10]

Controlling stereochemistry in polyketide synthesis: 1,3- vs. 1,2-asymmetric induction in methyl ketone aldol additions to β-super siloxy aldehydes

The aldol addition of methyl ketones to β-siloxy and α-methyl β-siloxy aldehydes is described. Careful control of mechanistically distinct aldol reactions leverages 1,2- and 1,3-asymmetric induction, selectively forming syn and anti aldol adducts with excellent diastereocontrol. Experimental and theoretical investigations have provided insight to the factors governing diastereoselectivity.

Stereodivergent Approach to the Avermectins Based on “Super Silyl” Directed Aldol Reactions

A stereodivergent approach to the spiroketal fragment of the avermectins is described. The strategy utilizes a sequence of three aldol reactions directed by the tris(trimethylsilyl)silyl “super silyl” group. Central to this strategy is that each aldol reaction can be controlled to allow access to either diastereomer in high stereoselectivity, thereby affording 16 stereoisomers along the same linear skeleton. The aldol products can be transformed into spiroketals, including an advanced intermediate in the total synthesis of avermectin A1a.

Kinetic characterization of the inhibition of protein tyrosine phosphatase-1B by Vanadyl (VO2+) chelates

Protein tyrosine phosphatases (PTPases) are a prominent focus of drug design studies because of their roles in homeostasis and disorders of metabolism. These studies have met with little success because (1) virtually all inhibitors hitherto exhibit only competitive behavior and (2) a consensus sequence H/V-C-X5-R-S/T characterizes the active sites of PTPases, leading to low specificity of active site directed inhibitors. With protein tyrosine phosphatase-1B (PTP1B) identifed as the target enzyme of the vanadyl (VO2+) chelate bis(acetylacetonato)oxidovanadium(IV) [VO(acac)2] in 3T3-L1 adipocytes [Ou et al. J Biol Inorg Chem 10: 874–886, 2005], we compared the inhibition of PTP1B by VO(acac)2 with other VO2+-chelates, namely, bis(2-ethyl-maltolato)oxidovanadium(IV) [VO(Et-malto)2] and bis(3-hydroxy-2-methyl-4(1H)pyridinonato)oxidovanadium(IV) [VO(mpp)2] under steady-state conditions, using the soluble portion of the recombinant human enzyme (residues 1–321). Our results differed from those of previous investigations because we compared inhibition in the presence of the nonspecific substrate p-nitrophenylphosphate and the phosphotyrosine-containing undecapeptide DADEpYLIPQQG mimicking residues 988–998 of the epidermal growth factor receptor, a relevant, natural substrate. While VO(Et-malto)2 acts only as a noncompetitive inhibitor in the presence of either subtrate, VO(acac)2 exhibits classical uncompetitive inhibition in the presence of DADEpYLIPQQG but only apparent competitive inhibition with p-nitrophenylphosphate as substrate. Because uncompetitive inhibitors are more potent pharmacologically than competitive inhibitors, structural characterization of the site of uncompetitive binding of VO(acac)2 may provide a new direction for design of inhibitors for therapeutic purposes. Our results suggest also that the true behavior of other inhibitors may have been masked when assayed with only p-nitrophenylphosphate as substrate.

Asymmetric Synthesis of α,β-Thioepoxy Carbonyls by Rhodium Catalysis

74 I . C AN O , E . G Ó M E Z B E N G O A, A . L AN D A, M . M A E S T R O, A . M I E L G O, I . OL A I Z OL A , M . O I A R B I D E , C . PA L O M O * ( UN I V E R S I D AD D E L P A Í S VA S C O , S A N SE B A S T I Á N A N D U N I V E R S I D A D E D A C O R U ÑA , S P A I N ) N-(Diazoacetyl)oxazolidin-2-thiones as Sulfur-Donor Reagents: Asymmetric Synthesis of Thiiranes from Aldehydes Angew. Chem. Int. Ed. 2012, 51, 10856–10860.

Asymmetric Synthesis of Indolines by Pd-Catalyzed C(sp3)–H Activation

Significance: The development of a new class of phosphine ligands and their application to asymmetric C–H activation is described. The ligand design incorporates several features that distinguish it from other chiral phosphine ligands: the phosphine is electron-rich, monodentate, highly tunable (R3 and R4 groups) and bears a C2-symmetric phospholane rather than P-centered chirality. These ligands display excellent reactivity and selectivity in the synthesis of the important indoline motif. Comment: Working under the hypothesis that the C–H activation step proceeds by a concerted deprotonation–metallation pathway, the authors screened various ligands and carboxylic acid cocatalysts. The bulky acid shown above was found to be optimal. The authors propose that the phosphine ligand induces a chiral environment through the spatial orientation of the carboxylate ligand. Indeed, chiral acids were also found to influence selectivity. Tf N