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1.  Alkane Desaturation via Concerted Double Hydrogen Atom Transfer to Benzyne 
Nature  2013;501(7468):10.1038/nature12492.
PMCID: PMC3818522  PMID: 24067712
2.  Synthesis of complex benzenoids via the intermediate generation of o-benzynes through the hexadehydro-Diels–Alder reaction 
Nature protocols  2013;8(3):501-508.
The hexadehydro-Diels–Alder (HDDA) cascade enables the synthesis of complex benzenoid products with various substitution patterns via aryne intermediates. The first stage of this cascade involves generation of a highly reactive ortho-benzyne intermediate by a net [4+2] cycloisomerization of a triyne substrate. The benzyne can be rapidly ‘trapped’ either intra- or intermolecularly with a myriad of nucleophilic or π-bond-donating reactants. As a representative example of a general procedure to synthesize highly substituted benzenoids, this protocol describes the synthesis of a typical triyne substrate and its use as the reactant in an HDDA cascade to form a phthalide. The synthetic procedure detailed herein (four chemical reactions) takes 16–20 h of active effort over a several day period for preparation of the triyne precursor and ~2 h of active effort over a 3-day period for generation and trapping of the benzyne and isolation of the phthalide product.
PMCID: PMC3895496  PMID: 23411632
HDDA; benzyne; Cadiot-Chodkiewicz; cascade; organic synthesis
3.  Oxyanionic Sigmatropic Rearrangements Relevant to Cyclooctadienone Formation in Penostatins I and F 
Organic letters  2012;14(18):4738-4741.
The results of several experiments designed to probe the energetic viability of a reaction path for generation of penostatins I (3) and F (4) via spontaneous [3,3]-sigmatropic rearrangement are reported. In particular, the enolate derived from the 2-vinyl-6-acyldihydropyran 8-cis gave cyclooctadienone 12 via facile anionic oxy-Claisen rearrangement, demonstrating the feasibility of such an event.
PMCID: PMC3501534  PMID: 22963036
4.  o-(Trialkylstannyl)anilines and Their Utility in Stille Cross-Coupling: Direct Introduction of the 2-Aminophenyl Substituent 
Tetrahedron letters  2012;53(37):4938-4941.
We have developed shelf- and air-stable ortho-stannylated aniline reagents that can directly be coupled with alkenyl and aryl halides via Stille cross-coupling. We report i) the efficient preparation of o-(tributylstannyl)aniline (2a) and o-(trimethylstannyl)aniline (2b), ii) the comparison of the reactivities of 2a and 2b with those of related organostannanes in cross-coupling reaction with an alkenyl halide, and iii) the cross-coupling of 2a and 2b with a series of arylhalides and triflate.
PMCID: PMC3439219  PMID: 22984300
Cross-coupling; Ortho-metalation; Aniline; Organostannanes
5.  Effects of block copolymer properties on nanocarrier protection from in vivo clearance 
Drug nanocarrier clearance by the immune system must be minimized to achieve targeted delivery to pathological tissues. There is considerable interest in finding in vitro tests that can predict in vivo clearance outcomes. In this work, we produce nanocarriers with dense PEG layers resulting from block copolymer-directed assembly during rapid precipitation. Nanocarriers are formed using block copolymers with hydrophobic blocks of polystyrene (PS), poly-ε-caprolactone (PCL), poly-D,L-lactide (PLA), or poly-lactide-co-glycolide (PLGA), and hydrophilic blocks of polyethylene glycol (PEG) with molecular weights from 1.5 kg/mol to 9 kg/mol. Nanocarriers with paclitaxel prodrugs are evaluated in vivo in Foxn1nu mice to determine relative rates of clearance. The amount of nanocarrier in circulation after 4 h varies from 10% to 85% of initial dose, depending on the block copolymer. In vitro complement activation assays are conducted in an effort to correlate the protection of the nanocarrier surface from complement binding and activation and in vivo circulation. Guidelines for optimizing block copolymer structure to maximize circulation of nanocarriers formed by rapid precipitation and directed assembly are proposed, relating to the relative size of the hydrophilic and hydrophobic block, the hydrophobicity of the anchoring block, the absolute size of the PEG block, and polymer crystallinity. The in vitro results distinguish between the poorly circulating PEG5k-PCL9k and the better circulating nanocarriers, but could not rank the better circulating nanocarriers in order of circulation time. Analysis of PEG surface packing on monodisperse 200 nm latex spheres indicates that the sizes of the hydrophobic PCL, PS, and PLA blocks are correlated with the PEG blob size, and possibly the clearance from circulation. Suggestions for next step in vitro measurements are made.
PMCID: PMC3416956  PMID: 22732478
nanocarrier; polyethylene glycol; complement activation; in vivo circulation; nanoparticle; block copolymer; polycaprolactone; polylactic acid; stealth
6.  Total synthesis of peloruside A via kinetic lactonization and relay RCM cyclization reactions (and identification of iso-peloruside A) 
A convergent total synthesis of peloruside A (1) is described. The key strategic features are a diastereoselective lactonization to generate a C5-C9 valerolactone from the C2-symmetric ketone 4, which comprises C1–C9 of 1, and a relay ring closing metathesis (RRCM) reaction to produce a dehydrovalerolactone 20, which embodies C13–C19. A new isomer of 1, the valerolactone iso-peloruside A (iso-1), was identified.
PMCID: PMC3740187  PMID: 20645374
aldol reaction; lactones; metathesis; relay ring closing metathesis (RRCM); total synthesis
7.  A Case Study of Empirical and Computational Chemical Shift Analyses: Reassignment of the Relative Configuration of Phomopsichalasin to that of Diaporthichalasin 
Journal of natural products  2012;75(7):1326-1331.
Phomopsichalasin was isolated and assigned structure 1 over 15 years ago. Analysis of its proton NMR data led us to hypothesize that not all aspects of the relative configuration of this structure were correct. We have used both empirical and computational methods to propose an alternative structure. Diaporthichalasin was reported several years ago, and its structure was assigned as 7, a diastereomer of structure 1, and confirmed by a single crystal X-ray study. We have shown that diaporthichalasin and phomopsichalasin are identical; i.e., both have structure 7. Additional aspects of NMR interpretation that provide guidance for avoiding some of the pitfalls that can lead to incorrect structure assignments are discussed. These recommendations/reminders include i) the use of complementary solvents for acquiring NMR data that break accidental chemical shift degeneracy, ii) the importance of assigning coupling constants as extensively as possible, and iii) exercising caution when interpreting correlations in 2D spectra where overlapping resonances are involved.
PMCID: PMC3428957  PMID: 22731865
8.  The hexadehydro-Diels–Alder reaction 
Nature  2012;490(7419):208-212.
o-Benzynes (arynes) are among the most versatile of all reactive (short-lived) intermediates in organic chemistry. These species can be trapped to give products that are valuable from the perspective of both fine (pharmaceuticals) and commodity (agrochemicals, dyes, polymers, etc.) chemicals. Here we show a fundamentally new strategy that unites a de novo generation of benzynes, through the title hexadehydro-Diels–Alder (HDDA) reaction, with their in situ elaboration into structurally complex benzenoid products. In the HDDA reaction a 1,3-diyne is engaged in a [4+2] cycloisomerization with a third (pendant) alkyne–the diynophile–to produce the highly reactive benzyne intermediate. The metal- and reagent-free reaction conditions for this simple, thermal transformation are notable. The subsequent and highly efficient trapping reactions increase the power of the overall process. Finally, we provide examples of how this de novo benzyne generation approach allows new modes of intrinsic reactivity to be revealed.
PMCID: PMC3538845  PMID: 23060191
9.  A Concise Total Synthesis of (±)- and (−)-Okilactomycin D 
Organic Letters  2012;14(3):828-831.
The spirotetronate okilactomycin D (7) has been efficiently synthesized by a route featuring a substrate-controlled, diastereoselective (8:1) intramolecular Diels-Alder (IMDA) reaction of 11. The assigned absolute configuration of (−)-7 was confirmed.
PMCID: PMC3272355  PMID: 22273402
10.  A Strategy for Control of “Random” Copolymerization of Lactide and Glycolide: Application to Synthesis of PEG-b-PLGA Block Polymers Having Narrow Dispersity 
Macromolecules  2011;44(18):7132-7140.
Poly(lactic-co-glycolic acid) (PLGA) is a biodegradable copolymer that is also acceptable for use in a variety of biomedical applications. Typically, a random PLGA polymer is synthesized in a bulk batch polymerization using a tin-based catalyst at high temperatures. This methodology results in relatively broad polydispersity indexes (PDIs) due to transesterification, and the polymer product is often discolored. We report here the use of 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU), a known, effective, and convenient organocatalyst for the ring-opening polymerization of cyclic esters, to synthesize random copolymers of lactide and glycolide. The polymerization kinetics of the homo- and copolymerizations of lactide and glycolide were explored via NMR spectroscopy. A novel strategy that employs a controlled addition of the more reactive glycolide monomer to a solution containing the lactide monomer, the poly(ethylene glycol) (PEG) macroinitiator, and DBU catalyst was developed. Using this tactic (semi-batch polymerization), we synthesized a series of block copolymers that exhibited excellent correlation of the expected and observed molecular weights and possessed narrow PDIs. We also measured the thermal properties of these block copolymers and observed trends based on the composition of the block copolymer. We also explored the need for experimental rigor in several aspects of the preparations and have identified a set of convenient reaction conditions that provide polymer products that retain the aforementioned desirable characteristics. These polymerizations proceed rapidly at room temperature and without the need for tin-based catalysts to provide PEG-b-PLGAs suitable for use in biomedical investigations.
PMCID: PMC3266509  PMID: 22287809
11.  Dual Macrolactonization/Pyran-Hemiketal Formation via Acylketenes [and its Application to Syntheses of (−)-Callipeltoside A and a Lyngbyaloside B Model System] 
Thermal generation of acylketenes in diol-containing substrates results in dual macrocyclization/pyran-hemiketal formation. This transformation expands the scope of acylketene macrolactonizations and their application to the synthesis of complex macrolides. Triol and even tetrol substrates also have been closed in highly regioselective fashion. Additionally, the challenging macrolactonization of a tertiary alcohol was achieved.
PMCID: PMC3408544  PMID: 18979468
acylketenes; regioselective macrolactonization; concerted addition
13.  Access to Functionalized Steroid Side Chains via Modified Julia Olefination 
Organic letters  2011;13(4):703-705.
Various functionalized steroidal side chains were conveniently accessed by a modified Julia olefination strategy using a common sulfone donor and an appropriate α-branched aldehyde acceptor. For the coupling of these hindered classes of reaction partners (and in contrast to typically observed trends), the benzothiazolyl(BT)-sulfone anion gave superior outcomes compared to the phenyltetrazolyl(PT)-sulfone anion.
PMCID: PMC3045753  PMID: 21244047
14.  Synthesis and olfactory activity of unnatural, sulfated 5β-bile acid derivatives in the sea lamprey (Petromyzon marinus) 
Steroids  2010;76(3):291-300.
A variety of unnatural bile acid derivatives (9a–9f) were synthesized and used to examine the specificity with which the sea lamprey (Petromyzon marinus) olfactory system detects these compounds. These compounds are analogs of petromyzonol sulfate (PS, 1), a component of the sea lamprey migratory pheromone. Both the stereochemical configuration at C5 (i.e., 5α vs. 5β) and the extent and sites of oxygenation (hydroxylation or ketonization) of the bile acid derived steroid skeleton were evaluated by screening the compounds for olfactory activity using electro-olfactogram recording. 5β-Petromyzonol sulfate (9a) elicited a considerable olfactory response at sub-nanomolar concentration. In addition, less oxygenated systems (i.e., 9b–9e) elicited olfactory responses, albeit with less potency. The sea lamprey sex pheromone mimic 9f (5β-3-ketopetromyzonol sulfate) was also examined and found to produce a much lower olfactory response. Mixture studies conducted with 9a and PS (1) suggest that stimulation is occurring via similar modes of activation, demonstrating a relative lack of specificity for recognition of the allo-configuration (i.e., 5α) in sea lamprey olfaction. This attribute could facilitate design of pheromone analogs to control this invasive species.
PMCID: PMC3062205  PMID: 21145335
steroid synthesis; olfactory SAR; pheromone; bile acid sulfates
15.  A Total Synthesis of (−)-Callipeltoside A 
The Journal of organic chemistry  2010;75(21):7052-7060.
A total synthesis of (−)-callipeltoside A (1) has been achieved. The core macrocycle was made via a dual macrolactonization/pyran hemiketal formation reaction, which was developed to circumvent issues related to the reversible nature of acylketene formation from β-keto lactone substrates. Initial approaches to the core of the natural product that revolved around ring-closing metathesis (RCM) and relay ring-closing metathesis (RRCM) reactions are also described.
PMCID: PMC3056157  PMID: 20932014
16.  Room Temperature Acylketene Formation? 1,3-Dioxin-4-ones via Silver(I) Activation of Phenylthioacetoacetate in the Presence of Ketones 
The Journal of organic chemistry  2010;75(17):6054-6056.
Silver (I) activation of thioacetoacetates in the presence of ketones produces 1,3-dioxin-4-ones. Mechanistic studies addressing the intermediacy of an acylketene intermediate are described.
PMCID: PMC3040570  PMID: 20690691
17.  Maleimide Functionalized Poly(ε-caprolactone)-b-poly(ethylene glycol) (PCL-PEG-MAL): Synthesis, Nanoparticle Formation, and Thiol Conjugation 
Carboxylic acid terminated poly(ε-caprolactone)s (PCL-COOHs) with narrow polydispersity were synthesized and coupled with poly(ethylene glycol) (HO-PEG-OH) to afford PCL-PEG-OH copolymers. The hydroxyl groups in the PCL-PEG-OHs were then converted to maleimide groups to afford maleimide terminated PCL-PEG-MALs that contained 70–90% maleimide functionality. Nanoparticles with maleimide functionality on their surfaces were prepared by impingement mixing. Particle sizes and size distributions were determined by dynamic light scattering. Conjugation of reduced glutathione with model maleimides and two MAL-functional nanoparticles was also demonstrated. The amount of accessible maleimide on the particle surface was measured using Ellman’s reagent to range between ~51–67%.
PMCID: PMC3128472  PMID: 21731402
block copolymer nanoparticles; biocompatible; glutathione conjugation; NMR spectroscopy
18.  Long-range Shielding Effects in the 1H NMR Spectra of Mosher-like Ester Derivatives 
Organic letters  2010;12(8):1768-1771.
The relative magnitudes of the chemical shift differences (Δδs) in the two diastereomers of menthyl esters of known chiral derivatizing agents (CDAs) were compared to those of the 〈-methoxy-〈-trifluoromethyl-1-naphthylacetyl (MTN(1)A) analogs I. Discrimination of the terminal diastereotopic methyl resonances in esters of the homologous, symmetrical carbinols II was evaluated. Remarkably, the methyls differed in the MTN(1)A esters III even when n = 15; an unexpected crossover in the sign of the Δδ values was also observed.
PMCID: PMC2886499  PMID: 20337423
19.  Dynamic Kinetic Resolution During a Vinylogous Payne Rearrangement: A Concise Synthesis of the Polar Pharmacophoric Subunit of (+)-Scyphostatin 
Organic letters  2010;12(1):52-55.
The diastereomeric epoxycyclohexenols 3a/b (obtained via a Wharton rearrangement of a bis-epoxycyclohexanone precursor) were shown to undergo interconversion via a facile vinylogous Payne rearrangement. Mechanistic issues were probed; the doubly O-deuterated analogs underwent this equilibration more slowly than the parent dihydroxy compounds. It was possible to kinetically resolve the mixture of 3a/b under equilibrating conditions by use of Amano PS. This DKR is additionally noteworthy because it sets four stereocenters in a single event.
PMCID: PMC2804749  PMID: 19968321
20.  Okundoperoxide, A Bicyclic Cyclofarnesylsesquiterpene Endoperoxide from Scleria striatinux with Antiplasmodial Activity 
Journal of natural products  2009;72(2):280-283.
Okundoperoxide (1) was isolated by bioassay-guided fractionation of extracts from Scleria striatinux (syn. S. striatonux) (Cyperaceae). The compound contains a cyclic endoperoxide structural moiety and possesses moderate antimalarial activity.
PMCID: PMC2765531  PMID: 19199815
21.  Diamino Telechelic Polybutadienes for Solventless Styrene-butadiene-styrene (SBS) Triblock Copolymer Formation 
Polymer  2008;49(24):5307-5313.
High molecular weight, high functionality diamino telechelic polybutadienes (TPBs) were synthesized by ring-opening metathesis polymerization (ROMP) of 1,5-cyclooctadiene (COD) in the presence of a chain transfer agent, 1,8-dicyano-4-octene, followed by lithium aluminum hydride reduction. Melt coupling of diamino TPB with anhydride-terminated polystyrene (PS-anh) resulted in the formation of styrene-butadiene-styrene (SBS) triblock copolymers; ca. 80% maximum conversion of PS-anh was achieved within 30 seconds. The results from SAXS, TEM, and rheological measurements of the coupling products confirmed the formation of SBS triblock copolymers having lamellar morphology. A fluororesent-labeled PS-anh was used to study the coupling kinetics by diluting the reactants by the addition of non-functional PS.
PMCID: PMC2607032  PMID: 19907636
ROMP; reactive melt blending; amine anhydride coupling
22.  Identification of Sesquiterpene Synthases from Nostoc punctiforme PCC 73102 and Nostoc sp. Strain PCC 7120▿ †  
Journal of Bacteriology  2008;190(18):6084-6096.
Cyanobacteria are a rich source of natural products and are known to produce terpenoids. These bacteria are the major source of the musty-smelling terpenes geosmin and 2-methylisoborneol, which are found in many natural water supplies; however, no terpene synthases have been characterized from these organisms to date. Here, we describe the characterization of three sesquiterpene synthases identified in Nostoc sp. strain PCC 7120 (terpene synthase NS1) and Nostoc punctiforme PCC 73102 (terpene synthases NP1 and NP2). The second terpene synthase in N. punctiforme (NP2) is homologous to fusion-type sesquiterpene synthases from Streptomyces spp. shown to produce geosmin via an intermediate germacradienol. The enzymes were functionally expressed in Escherichia coli, and their terpene products were structurally identified as germacrene A (from NS1), the eudesmadiene 8a-epi-α-selinene (from NP1), and germacradienol (from NP2). The product of NP1, 8a-epi-α-selinene, so far has been isolated only from termites, in which it functions as a defense compound. Terpene synthases NP1 and NS1 are part of an apparent minicluster that includes a P450 and a putative hybrid two-component protein located downstream of the terpene synthases. Coexpression of P450 genes with their adjacent located terpene synthase genes in E. coli demonstrates that the P450 from Nostoc sp. can be functionally expressed in E. coli when coexpressed with a ferredoxin gene and a ferredoxin reductase gene from Nostoc and that the enzyme oxygenates the NS1 terpene product germacrene A. This represents to the best of our knowledge the first example of functional expression of a cyanobacterial P450 in E. coli.
PMCID: PMC2546793  PMID: 18658271

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