Synergy of synthesis, computation and NMR reveals correct baulamycin structures.

Small-molecule, biologically active natural products continue to be our most rewarding source of, and inspiration for, new medicines. Sometimes we happen upon such molecules in minute quantities in unique, difficult-to-reach, and often fleeting environments, perhaps never to be discovered again. In these cases, determining the structure of a molecule-including assigning its relative and absolute configurations-is paramount, enabling one to understand its biological activity. Molecules that comprise stereochemically complex acyclic and conformationally flexible carbon chains make such a task extremely challenging. The baulamycins (A and B) serve as a contemporary example. Isolated in small quantities and shown to have promising antimicrobial activity, the structure of the conformationally flexible molecules was determined largely through J-based configurational analysis, but has been found to be incorrect. Our subsequent campaign to identify the true structures of the baulamycins has revealed a powerful method for the rapid structural elucidation of such molecules. Specifically, the prediction of nuclear magnetic resonance (NMR) parameters through density functional theory-combined with an efficient sequence of boron-based synthetic transformations, which allowed an encoded (labelled) mixture of natural-product diastereomers to be prepared-enabled us rapidly to pinpoint and synthesize the correct structures.

Conformationally Controlled sp3 -Hydrocarbon-Based α-Helix Mimetics.

With over 60 % of protein-protein interfaces featuring an α-helix, the use of α-helix mimetics as inhibitors of these interactions is a prevalent therapeutic strategy. However, methods to control the conformation of mimetics, thus enabling maximum efficacy, can be restrictive. Alternatively, conformation can be controlled through the introduction of destabilizing syn-pentane interactions. This tactic, which is often adopted by Nature, is not a common feature of lead optimization owing to the significant synthetic effort required. Through assembly-line synthesis with NMR and computational analysis, we have shown that alternating syn-anti configured contiguously substituted hydrocarbons, by avoiding syn-pentane interactions, adopt well-defined conformations that present functional groups in an arrangement that mimics the α-helix. The design of a p53 mimetic that binds to Mdm2 with moderate to good affinity, demonstrates the therapeutic promise of these scaffolds.

Conformationally Controlled Linear and Helical Hydrocarbons Bearing Extended Side Chains.

Conformationally controlled flexible molecules are ideal for applications in medicine and materials, where shape matters but an ability to adapt to multiple and changing environments is often required. The conformation of flexible hydrocarbon chains bearing contiguous methyl substituents is controlled through the avoidance of syn-pentane interactions: alternating syn-anti isomers adopt a linear conformation while all-syn isomers adopt a helical conformation. From a simple diamond lattice analysis, larger substituents, which would be required for most potential applications, result in significant and unavoidable syn-pentane interactions, suggesting substantially reduced conformational control. Through a combination of computation, synthesis, and NMR analysis, we have identified a selection of substitution patterns that allow large groups to be incorporated on conformationally controlled linear and helical hydrocarbon chains. Surprisingly, when the methyl substituents of alternating syn-anti hydrocarbons are replaced with acetoxyethyl groups, the main chain of almost 95% of the population of molecules adopt a linear conformation. Here, the side chains adopt nonideal eclipsed conformations with the main chain, thus minimizing syn-pentane interactions. In the case of all-syn hydrocarbons, concurrent removal of some methyl groups on the main chain adjacent to the large substituents is required to maintain a high population of molecules adopting a helical conformation. This information can now be used to design flexible hydrocarbon chains displaying functional groups in a defined relative orientation for multivalent binding or cooperative reactivity, for example, in targeting the interfaces defined by disease-relevant protein-protein interactions.

Ring-Opening Lithiation-Borylation of 2-Trifluoromethyl Oxirane: A Route to Versatile Tertiary Trifluoromethyl Boronic Esters.

Stereogenic trifluoromethyl-substituted carbon centers are highly sought-after moieties in pharmaceutical and agrochemical discovery. Here, we show that lithiation-borylation reactions of 2-trifluoromethyl oxirane give densely functionalized and highly versatile trifluoromethyl-substituted α-tertiary boronic esters. The intermediate boronate complexes undergo the desired 1,2-rearrangement of the carbon-based group with complete retentive stereospecificity, a process that was only observed in non-polar solvents in the presence of TESOTf. Although the trifluoromethyl group adversely affects subsequent transformations of the α-boryl group, Zweifel olefinations provide trifluoromethyl-bearing quaternary stereocenters substituted with alkenes, alkynes and ketones.

Catalysis of Hydrogen-Deuterium Exchange Reactions by 4-Substituted Proline Derivatives.

The identification and understanding of structure-activity relationships is vital for rational catalyst design. A kinetic study of the hydrogen-deuterium exchange reaction of cyclohexanone in aqueous solution, as catalyzed by proline derivatives, has revealed valuable structure-activity relationships. In phosphate-buffered solution, cis-4-fluoroproline is more active than the trans isomer, a distinction that appears to originate from a destabilizing interaction between the fluorine atom and phosphate anion during general acid-catalyzed dehydration of the carbinolamine intermediate. trans-4-Ammoniumprolines are exceptionally active catalysts owing to favorable Coulombic interactions involving the ammonium group and the alkoxide moiety formed upon 1,2-addition of the proline derivative to the ketone. These results could be used for the optimization of proline catalysts, especially in transformations where the formation of the putative iminium ion is rate-limiting.

Investigation of the Deprotonative Generation and Borylation of Diamine-Ligated α-Lithiated Carbamates and Benzoates by in Situ IR spectroscopy.

Diamine-mediated α-deprotonation of O-alkyl carbamates or benzoates with alkyllithium reagents, trapping of the carbanion with organoboron compounds, and 1,2-metalate rearrangement of the resulting boronate complex are the primary steps by which organoboron compounds can be stereoselectively homologated. Although the final step can be easily monitored by 11B NMR spectroscopy, the first two steps, which are typically carried out at cryogenic temperatures, are less well understood owing to the requirement for specialized analytical techniques. Investigation of these steps by in situ IR spectroscopy has provided invaluable data for optimizing the homologation reactions of organoboron compounds. Although the deprotonation of benzoates in noncoordinating solvents is faster than that in ethereal solvents, the deprotonation of carbamates shows the opposite trend, a difference that has its origin in the propensity of carbamates to form inactive parasitic complexes with the diamine-ligated alkyllithium reagent. Borylation of bulky diamine-ligated lithiated species in toluene is extremely slow, owing to the requirement for initial complexation of the oxygen atoms of the diol ligand on boron with the lithium ion prior to boron-lithium exchange. However, ethereal solvent, or very small amounts of THF, facilitate precomplexation through initial displacement of the bulky diamines coordinated to the lithium ion. Comparison of the carbonyl stretching frequencies of boronates derived from pinacol boronic esters with those derived from trialkylboranes suggests that the displaced lithium ion is residing on the pinacol oxygen atoms and the benzoate/carbamate carbonyl group, respectively, explaining, at least in part, the faster 1,2-metalate rearrangements of boronates derived from the trialkylboranes.

Visible-Light-Mediated Decarboxylative Radical Additions to Vinyl Boronic Esters: Rapid Access to γ-Amino Boronic Esters.

The synthesis of alkyl boronic esters by direct decarboxylative radical addition of carboxylic acids to vinyl boronic esters is described. The reaction proceeds under mild photoredox catalysis and involves an unprecedented single-electron reduction of an α-boryl radical intermediate to the corresponding anion. The reaction is amenable to a diverse range of substrates, including α-amino, α-oxy, and alkyl carboxylic acids, thus providing a novel method to rapidly access boron-containing molecules of potential biological importance.

Enantiodivergent Synthesis of Allenes by Point-to-Axial Chirality Transfer.

An enantiodivergent method for the synthesis of multiply substituted allenes is described. Highly enantioenriched, point-chiral boronic esters were synthesized by homologation of α-seleno alkenyl boronic esters with lithiated carbamates and eliminated to form axially chiral allene products. By employing either oxidative or alkylative conditions, both syn and anti elimination could be achieved with complete stereospecificity. The process enables the synthesis of either M or P allenes from a single isomer of a point-chiral precursor and can be employed for the enantioselective assembly of di-, tri-, and tetrasubstituted allenes.

Enantiospecific Synthesis of ortho-Substituted Benzylic Boronic Esters by a 1,2-Metalate Rearrangement/1,3-Borotropic Shift Sequence.

Coupling reactions between benzylamines and boronic esters have been investigated. ortho-Lithiated benzylamines react with boronic esters and a N-activator to afford ortho-substituted benzylic boronic esters with formal 1,1'-benzylidene insertion into the C-B bond. The reaction occurs by a SN2' elimination and 1,2-metalate rearrangement of the N-activated boronate complex to afford a dearomatized intermediate, which undergoes a Lewis-acid catalyzed 1,3-borotropic shift to afford the boronic ester products in high yield and with excellent enantiospecificity. The use of enantioenriched α-substituted benzylamines gave the corresponding secondary boronic esters with high ee.

α-Sulfinyl Benzoates as Precursors to Li and Mg Carbenoids for the Stereoselective Iterative Homologation of Boronic Esters.

The stereoselective reagent-controlled homologation of boronic esters is one of a small number of iteratable synthetic transformations that if automated could form the basis of a veritable molecule-making machine. Recently, α-stannyl triisopropylbenzoates and α-sulfinyl chlorides have emerged as useful building blocks for the iterative homologation of boronic esters. However, α-stannyl benzoates need to be prepared using stoichiometric amounts of the (+)- or (-)-enantiomer of the scarcely available and expensive diamine sparteine; also, these building blocks, together with the byproducts that are generated during homologation, are perceived as being toxic. On the other hand, α-sulfinyl chlorides are difficult to prepare with high levels of enantiopurity and are prone to undergo deleterious acid-base side-reactions under the reaction conditions for homologation, leading to low stereospecificity. Here, we show that the use of a hybrid of these two building blocks, namely, α-sulfinyl triisopropylbenzoates, largely overcomes the above drawbacks. Through either the sulfinylation of α-magnesiated benzoates with either enantiomer of Andersen's readily available menthol-derived sulfinate or the α-alkylation of enantiopure S-chiral α-sulfinyl benzoates, we have prepared a range of highly enantiopure mono- and disubstituted α-sulfinyl benzoates, some bearing sensitive functional groups. Barbier-type reaction conditions have been developed that allow these building blocks to be converted into lithium (t-BuLi) and magnesium (i-PrMgCl·LiCl) carbenoids in the presence of boronic esters, thus allowing efficient and highly stereospecific homologation. The use of magnesium carbenoids allows carbon chains to be grown with the incorporation of sensitive functional groups, such as alkyl/aryl halides, azides, and esters. The use of lithium carbenoids, which are less sensitive to steric hindrance, allows sterically encumbered carbon-carbon bonds to be forged. We have also shown that these building blocks can be used consecutively in three- and four-step iterative homologation processes, without intervening column chromatography, to give contiguously substituted carbon chains with very high levels of enantio- and diastereoselectivity.

Enantioselective Rhodium(III)-Catalyzed Markovnikov Hydroboration of Unactivated Terminal Alkenes.

We report the first enantioselective Rh-catalyzed Markovnikov hydroboration of unactivated terminal alkenes. Using a novel sp2-sp3 hybridized diboron reagent and water as a proton source, a broad range of alkenes undergo hydroboration to provide secondary boronic esters with high regio- and enantiocontrol.

Asymmetric Synthesis of Secondary and Tertiary Boronic Esters.

Non-racemic chiral boronic esters are recognised as immensely valuable building blocks in modern organic synthesis. Their stereospecific transformation into a variety of functional groups-from amines and halides to arenes and alkynes-along with their air and moisture stability, has established them as an important target for asymmetric synthesis. Efforts towards the stereoselective synthesis of secondary and tertiary alkyl boronic esters have spanned over five decades and are underpinned by a wealth of reactivity platforms, drawing on the unique and varied reactivity of boron. This Review summarizes strategies for the asymmetric synthesis of alkyl boronic esters, from the seminal hydroboration methods of H. C. Brown to the current state of the art.

Stereodivergent Olefination of Enantioenriched Boronic Esters.

A stereodivergent coupling reaction between vinyl halides and boronic esters is described. This coupling process proceeds without a transition-metal catalyst, instead proceeding by electrophilic selenation or iodination of a vinyl boronate complex followed by stereospecific syn or anti elimination. Chiral, nonracemic boronic esters could be coupled with complete enantiospecificity. The process enables the highly stereoselective synthesis of either the E or Z alkene from a single isomer of a vinyl coupling partner.

Enantiospecific Alkynylation of Alkylboronic Esters.

Enantioenriched secondary and tertiary alkyl pinacolboronic esters undergo enantiospecific deborylative alkynylation through a Zweifel-type alkenylation followed by a 1,2-elimination reaction. The process involves use of α-lithio vinyl bromide or vinyl carbamate species, for which application to Zweifel-type reactions has not previously been explored. The resulting functionalized 1,1-disubstituted alkenes undergo facile base-mediated elimination to generate terminal alkyne products in high yield and excellent levels of enantiospecificity over a wide range of pinacolboronic ester substrates. Furthermore, along with terminal alkynes, internal and silyl-protected alkynes can be formed by simply introducing a suitable carbon- or silicon-based electrophile after the base-mediated 1,2-elimination reaction.

Regio- and Stereoselective Homologation of 1,2-Bis(Boronic Esters): Stereocontrolled Synthesis of 1,3-Diols and Sch 725674.

1,2-Bis(boronic esters), derived from the enantioselective diboration of terminal alkenes, can be selectively homologated at the primary boronic ester by using enantioenriched primary/secondary lithiated carbamates or benzoates to give 1,3-bis(boronic esters), which can be subsequently oxidized to the corresponding secondary-secondary and secondary-tertiary 1,3-diols with full stereocontrol. The transformation was applied to a concise total synthesis of the 14-membered macrolactone, Sch 725674. The nine-step synthetic route also features a novel desymmetrizing enantioselective diboration of a divinyl carbinol derivative and high-yielding late-stage cross-metathesis and Yamaguchi macrolactonization reactions.

Total synthesis of the proposed structure of trichodermatide A.

A short total synthesis of the published structure of racemic trichodermatide A is reported. Our synthesis involves a Knoevenagel condensation/Michael addition sequence, followed by the formation of tricyclic hexahydroxanthene-dione and a diastereoselective bis-hydroxylation. The final product, the structure of which was confirmed by X-ray crystallography, has NMR spectra that are very similar, but not identical, to those of the isolated natural product. Quantum chemically computed (13)C shifts agree well with the present NMR measurements.

Clinical, MRI, and PET-CT criteria used by surgeons to determine suitability for pelvic exenteration surgery for recurrent rectal cancers: a Delphi study.

BACKGROUND: Surgical resection with clear margins is the major predictor of long-term survival in recurrent rectal cancer. The extent of pelvic exenteration surgery depends on many factors including clinical and radiological criteria. OBJECTIVE: The aim of this study was to establish which clinical, MRI, and PET criteria were considered important by surgeons who perform pelvic exenteration surgery, when assessing a patient with recurrent rectal cancer for pelvic exenteration surgery. DESIGN: A 2-stage Delphi study was conducted among an international panel of 36 colorectal surgeons recruited via a snowball-sampling method. Surgeons rated the importance of 99 clinical and radiological criteria by using a 9-point scale. MAIN OUTCOME MEASURES: Consensus was attained when at least 85% of the panel rated criteria within 3 points. RESULTS: Clinical factors suggestive of systemic disease, symptoms of advanced local recurrence such as pain, surgical fitness, and cognitive impairment were considered important by the panel when considering suitability for surgery. Agreement regarding the indication for surgery was reached for 20 radiological factors. Strong agreement was achieved for factors associated with tumor involvement in the axial and anterior compartments. For only 16 of these 20 radiological factors was there an agreement that a clear resection margin was likely to be achieved. LIMITATIONS: Further rounds of Delphi may have yielded greater consensus. CONCLUSION: This study has identified a set of criteria considered by experts to be important in evaluating patients' suitability for pelvic exenteration surgery. Evaluation of these criteria is required to determine their clinical utility in predicting a negative resection margin at pelvic exenteration surgery.

Iterative synthesis of 1,3-polyboronic esters with high stereocontrol and application to the synthesis of bahamaolide A.

Polyketide natural products often contain common repeat motifs, for example, propionate, acetate and deoxypropionate, and so can be synthesized by iterative processes. We report here a highly efficient iterative strategy for the synthesis of polyacetates based on boronic ester homologation that does not require functional group manipulation between iterations. This process involves sequential asymmetric diboration of a terminal alkene, forming a 1,2-bis(boronic ester), followed by regio- and stereoselective homologation of the primary boronic ester with a butenyl metallated carbenoid to generate a 1,3-bis(boronic ester). Each transformation independently controls the stereochemical configuration, making the process highly versatile, and the sequence can be iterated prior to stereospecific oxidation of the 1,3-polyboronic ester to yield the 1,3-polyol. This methodology has been applied to a 14-step synthesis of the oxopolyene macrolide bahamaolide A, and the versatility of the 1,3-polyboronic esters has been demonstrated in various stereospecific transformations, leading to polyalkenes, -alkynes, -ketones and -aromatics with full stereocontrol.

A predictive model of suitability for minimally invasive parathyroid surgery in the treatment of primary hyperparathyroidism [corrected].

BACKGROUND: Improved preoperative localizing studies have facilitated minimally invasive approaches in the treatment of primary hyperparathyroidism (PHPT). Success depends on the ability to reliably select patients who have PHPT due to single-gland disease. We propose a model encompassing preoperative clinical, biochemical, and imaging studies to predict a patient's suitability for minimally invasive surgery. METHODS: For the purposes of the present study, 180 consecutive patients were included for analysis. A 5-variable model based on preoperative ionized serum calcium (>1.4 mmol/l), intact parathyroid hormone level (≥ 2 times the upper limit of normal), positive sestamibi scan for a single affected gland, positive ultrasound scan for a single gland, and concordance between the two imaging modalities for single-gland disease at a similar location was employed, where a score of 1 was allocated for each variable present. RESULTS: Of the 180 patients, 62 (34%) underwent bilateral exploration, 63 (36%) underwent unilateral exploration, and 55 (30%) underwent minimally invasive parathyroidectomy. The results showed that 92% had single-gland disease, 3% had double adenomas, and 5% had hyperplasia. Biochemical cure was achieved in 98.9%. Mean follow-up was 153 days (range: 80-342 days). With the predictive scoring model, a score of ≥ 3 had a positive predictive value of 100% for single-gland disease. CONCLUSIONS: A scoring model encompassing preoperative biochemical and imaging data can be successfully employed to predict suitability for minimally invasive surgery in the majority of patients with single-gland disease.