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Gain-of-function mutations in leucine-rich kinase 2 (LRRK2) are associated with increased incidence of Parkinson disease (PD); thus, pharmacological inhibition of LRRK2 kinase activity is postulated as a disease-modifying treatment of PD. Histomorphological changes in lungs of nonhuman primates (NHPs) treated with small-molecule LRRK2 kinase inhibitors have brought the safety of this treatment approach into question. Although it remains unclear how LRRK2 kinase inhibition affects the lung, continued studies in NHPs prove to be both cost- and resource-prohibitive. To develop a tractable alternative animal model platform, we dosed male mice in-diet with the potent, highly selective LRRK2 kinase inhibitor MLi-2 and induced histomorphological changes in lung within 1 week. Oral bolus dosing of MLi-2 at a frequency modeled to provide steady-state exposure equivalent to that achieved with in-diet dosing induced type II pneumocyte vacuolation, suggesting pulmonary changes require sustained LRRK2 kinase inhibition. Treating mice with MLi-2 in-diet for up to 6 months resulted in type II pneumocyte vacuolation that progressed only modestly over time and was fully reversible after withdrawal of MLi-2. Immunohistochemical analysis of lung revealed a significant increase in prosurfactant protein C staining within type II pneumocytes. In the present study, we demonstrated the kinetics for onset, progression, and rapid reversibility of chronic LRRK2 kinase inhibitor effects on lung histomorphology in rodents and provide further evidence for the derisking of safety and tolerability concerns for chronic LRRK2 kinase inhibition in PD. SIGNIFICANCE STATEMENT We have defined a mouse model by which the on-target lung effects of leucine-rich kinase 2 (LRRK2) kinase inhibition can be monitored, whereas previous in vivo testing relied solely on nonhuman primates. Data serve to derisk long-term treatment with LRRK2 kinase inhibitors, as all lung changes were mild and readily reversible.

The discovery of potent, kinome selective, brain penetrant LRRK2 inhibitors is the focus of extensive research seeking new, disease-modifying treatments for Parkinson's disease (PD). Herein, we describe the discovery and evolution of a picolinamide-derived lead series. Our initial optimization efforts aimed at improving the potency and CLK2 off-target selectivity of compound 1 by modifying the heteroaryl C-H hinge and linker regions. This resulted in compound 12 which advanced deep into our research operating plan (ROP) before heteroaryl aniline metabolite 14 was characterized as Ames mutagenic, halting its progression. Strategic modifications to our ROP were made to enable early de-risking of putative aniline metabolites or hydrolysis products for mutagenicity in Ames. This led to the discovery of 3,5-diaminopyridine 15 and 4,6-diaminopyrimidine 16 as low risk for mutagenicity (defined by a 3-strain Ames negative result). Analysis of key matched molecular pairs 17 and 18 led to the prioritization of the 3,5-diaminopyridine sub-series for further optimization due to enhanced rodent brain penetration. These efforts culminated in the discovery of ethyl trifluoromethyl pyrazole 23 with excellent LRRK2 potency and expanded selectivity versus off-target CLK2.

This work describes an expedient access to sp3-rich nitrogen heterocycles via mild photoredox cleavage of 4-alkyl-1,4-dihydropyridines followed by cyclization of the resultant carbon-centered radicals with tethered imines., A large proportion of medicinally relevant molecules bear nitrogen and sp3-hybridized carbon functionalities. Overwhelmingly, these atoms are found as part of (hetero)cyclic structures. Despite their importance, synthetic approaches to saturated nitrogen heterocycles are limited to several established stoichiometric alkylation techniques, as well as a few methods involving C–H bond activation. The synthetic community remains interested in more general, mild, and sustainable ways to access these motifs. Here we describe a dual-catalyst system composed of an iridium photocatalyst and a lithium phosphate base that is capable of selectively homolyzing the N–H bond of 4-alkyl-1,4-dihydropyridines, presumably by proton-coupled-electron-transfer (PCET), and mediating efficient cyclization of the resultant carbon-centered radicals with tethered imines. The outcome of this transformation is access to a broad range of structurally complex nitrogen heterocycles obtainable from simple aldehyde starting materials in a highly chemoselective manner.

This paper describes an intermolecular cross-selective [2 + 2] photocycloaddition reaction of exocyclic arylidene oxetanes, azetidines, and cyclobutanes with simple electron-deficient alkenes. The reaction takes place under mild conditions using a commercially available Ir(III) photosensitizer upon blue light irradiation. This transformation provides access to a range of polysubstituted 2-oxaspiro[3.3]heptane, 2-azaspiro[3.3]heptane, and spiro[3.3]heptane motifs, which are of prime interest in medicinal chemistry as gem-dimethyl and carbonyl bioisosteres. A variety of further transformations of the initial cycloadducts are demonstrated to highlight the versatility of the products and enable selective access to either of a syn- or an anti-diastereoisomer through kinetic or thermodynamic epimerization, respectively. Mechanistic experiments and DFT calculations suggest that this reaction proceeds through a sensitized energy transfer pathway.

Retinoic acid receptor-related orphan nuclear receptor (ROR) γt is a member of the RORC nuclear hormone receptor family of transcription factors. RORγt functions as a critical regulator of thymopoiesis and immune responses. RORγt is expressed in multiple immune cell populations including Th17 cells, where its primary function is regulation of immune responses to bacteria and fungi through IL-17A production. However, excessive IL-17A production has been linked to numerous autoimmune diseases. Moreover, Th17 cells have been shown to elicit both pro- and anti-tumor effects. Thus, modulation of the RORγt/IL-17A axis may represent an attractive therapeutic target for the treatment of autoimmune disorders and some cancers. Herein we report the design, synthesis and characterization of three selective allosteric RORγt inhibitors in preclinical models of inflammation and tumor growth. We demonstrate that these compounds can inhibit Th17 differentiation and maintenance in vitro and Th17-dependent inflammation and associated gene expression in vivo, in a dose-dependent manner. Finally, RORγt inhibitors were assessed for efficacy against tumor formation. While, RORγt inhibitors were shown to inhibit tumor formation in pancreatic ductal adenocarcinoma (PDAC) organoids in vitro and modulate RORγt target genes in vivo, this activity was not sufficient to delay tumor volume in a KP/C human tumor mouse model of pancreatic cancer.

Intermolecular C-C bond-forming reactions are underdeveloped transformations in the field of biocatalysis. Here we report a photoenzymatic intermolecular hydroalkylation of olefins catalyzed by flavin-dependent 'ene'-reductases. Radical initiation occurs via photoexcitation of a rare high-order enzyme-templated charge-transfer complex that forms between an alkene, α-chloroamide, and flavin hydroquinone. This unique mechanism ensures that radical formation only occurs when both substrates are present within the protein active site. This active site can control the radical terminating hydrogen atom transfer, enabling the synthesis of enantioenriched γ-stereogenic amides. This work highlights the potential for photoenzymatic catalysis to enable new biocatalytic transformations via previously unknown electron transfer mechanisms.

[Image: see text] Preclinical optimization of compounds toward viable drug candidates requires an integrated understanding of properties that impact predictions of the clinically efficacious dose. The importance of optimizing half-life, unbound clearance, and potency and how they impact dose predictions are discussed in this letter. Modest half-life improvements for short half-life compounds can dramatically lower the efficacious dose. The relationship between dose and half-life is nonlinear when unbound clearance is kept constant, whereas the relationship between dose and unbound clearance is linear when half-life is kept constant. Due to this difference, we show that dose is more sensitive to changes in half-life than changes in unbound clearance when half-lives are shorter than 2 h. Through matched molecular pair analyses, we also show that the strategic introduction of halogens is likely to increase half-life and lower projected human dose even though increased lipophilicity does not guarantee extended half-life.

The kinase-activating mutation G2019S in leucine-rich repeat kinase 2 (LRRK2) is one of the most common genetic causes of Parkinson's disease (PD) and has spurred development of LRRK2 inhibitors. Preclinical studies have raised concerns about the safety of LRRK2 inhibitors due to histopathological changes in the lungs of nonhuman primates treated with two of these compounds. Here, we investigated whether these lung effects represented on-target pharmacology and whether they were reversible after drug withdrawal in macaques. We also examined whether treatment was associated with pulmonary function deficits. We conducted a 2-week repeat-dose toxicology study in macaques comparing three different LRRK2 inhibitors: GNE-7915 (30 mg/kg, twice daily as a positive control), MLi-2 (15 and 50 mg/kg, once daily), and PFE-360 (3 and 6 mg/kg, once daily). Subsets of animals dosed with GNE-7915 or MLi-2 were evaluated 2 weeks after drug withdrawal for lung function. All compounds induced mild cytoplasmic vacuolation of type II lung pneumocytes without signs of lung degeneration, implicating on-target pharmacology. At low doses of PFE-360 or MLi-2, there was ~50 or 100% LRRK2 inhibition in brain tissue, respectively, but histopathological lung changes were either absent or minimal. The lung effect was reversible after dosing ceased. Lung function tests demonstrated that the histological changes in lung tissue induced by MLi-2 and GNE-7915 did not result in pulmonary deficits. Our results suggest that the observed lung effects in nonhuman primates in response to LRRK2 inhibitors should not preclude clinical testing of these compounds for PD.

Parkinson's Disease (PD) is the second most common neurodegenerative disorder. Clinical approaches to manage PD include symptomatic therapies, serving to compensate for the effects of dopaminergic neuronal deficits, as well as more recently a move toward disease modification, with the goal of slowing or stopping disease progression. This perspective surveys the approved therapies for PD treatment as well as provides a view of the ongoing clinical approaches aimed at improving outcomes for PD patients.

Spleen tyrosine kinase (SYK) is a key activator of signaling pathways downstream of multiple surface receptors implicated in asthma. SYK function has been extensively studied in mast cells downstream of the high-affinity IgE receptor, FcεR1. Preclinical studies have demonstrated a role for SYK in models of allergic inflammation, but a role in airway constriction has not been demonstrated. Here, we have used a potent and selective pharmacological inhibitor of SYK to determine the role of SYK in allergen-mediated inflammation and airway constriction in preclinical models. Attenuation of allergic airway responses was evaluated in a rat passive anaphylaxis model and rat and sheep inhaled allergen challenge models, as well as an ex vivo model of allergen-mediated airway constriction in rats and cynomolgus monkeys. Pharmacological inhibition of SYK dose-dependently blocked IgE-mediated tracheal plasma extravasation in rats. In a rat ovalbumin-sensitized airway challenge model, oral dosing with an SYK inhibitor led to a dose-dependent reduction in lung inflammatory cells. Ex vivo analysis of allergen-induced airway constriction in ovalbumin-sensitized brown Norway rats showed a complete attenuation with treatment of a SYK inhibitor, as well as a complete block of allergen-induced serotonin release. Similarly, allergen-mediated airway constriction was attenuated in ex vivo studies from nonhuman primate lungs. Intravenous administration of an SYK inhibitor attenuated both early- and late-phase allergen-induced increases in airway resistance in an Ascaris-sensitive sheep allergen challenge model. These data support a key role for SYK signaling in mediating allergic airway responses.

Brevetoxin A is a decacyclic ladder toxin that possesses five-,six-, seven-, eight-, and nine-membered oxacycles, as well as 22 tetrahedral stereocenters. Herein, we describe a unified approach to the B, E, G, and J rings predicated upon a ring-closing metathesis strategy from the corresponding dienes. The enolate technologies developed in our laboratory allowed access to the precursor acyclic dienes for the B, E, and G medium ring ethers. The strategies developed for the syntheses of these four monocycles ultimately provided multigram quantities of each of the rings, supporting our efforts toward the convergent completion of brevetoxin A.

The C2-C11 cyclized cembranoids, which include the eunicellins (also known as the cladiellins), briarellins, asbestinins, and sarcodictyins, are secondary metabolites isolated from gorgonian octocorals and soft corals. An unusual oxatricyclic ring system containing a hydroisobenzofuran and an oxonene unit with stereogenic centers residing at C1-3, 9, 10, and 14 is common to the eunicellins, briarellins, and asbestinins. However, the location of the cyclohexyl methyl groups (C11 versus C12) and the oxidation level of the sixand nine-membered rings differ among the three classes. Faulkner has proposed that the cyclization of the cembranoid diterpene skeleton initiates a biosynthetic pathway that leads to all four subclasses of these unusual molecules (Figure 1). Beginning with the cembrane skeleton, C2-C11 cyclization provides the cladiellin framework. An intramolecular etherification of the cladiellin tricycle affords the tetracyclic framework of the briarellin subclass, and a subsequent 1,2-suprafacial methyl shift of the briarellin structure is postulated to deliver the asbestinins as the class that is furthest evolved from the cembrane skeleton. The presence of multiple structural types in a common organism provides circumstantial evidence for Faulkner’s proposed biosynthetic pathway. The isolation of a cembrane metabolite with cladiellin metabolites in Alcyonium molle and with asbestinin metabolites in Briareum steckii are specific examples. The sarcodictyins are also proposed to arise from a C2-C11 cyclization of the cembrane skeleton; however, in these systems, the cyclization results in a fused cyclohexane and oxonane in place of the hydroisobenzofuran of the cladiellins, briarellins, and asbestinins. As a result of this significant structural variation of the sarcodictyins, the synthetic approaches to these molecules are quite different than those for the other three related subclasses. This review will cover efforts toward the eunicellins, briarellins, and asbestinins but will not cover efforts toward the total synthesis of the sarcodictyins. Eunicellin was the first reported member of the C2-C11 cyclized cembranoid natural products, isolated in 1968 by Djerassi and co-workers from the soft coral Eunicella stricta found off the coast of Banyuls-sur-Mer in France. Since this discovery, over 100 unique secondary metabolites of gorgonian octocorals have been characterized, including the first asbestinin in 1980 and the first briarellin in 1995. A wide range of structural diversity is displayed by this group of marine natural products. The natural role of these cembranoids is proposed, based upon mollusk and fish lethality assays, to involve predation deterrence. Upon further investigation, several of the members of these subclasses have demonstrated significant pharmacological potential. Particularly, these diterpenes have been shown to exhibit in vitro cytotoxicity against various cancer cell lines, anti-inflammatory properties, antimicrobial activities, and histamine and acetylcholine antagonism. The fascinating molecular architecture of these cembranoids, as well as their potential as therapeutic agents, has sparked much interest in the synthetic community over the past decade. A variety of approaches toward these challenging structural motifs have been investigated and several total syntheses have been accomplished. Efforts toward the total synthesis of the cladiellins, briarellins, and asbestinins are the subject of this review.

The enantioselective total syntheses of 11-acetoxy-4-deoxyasbestinin D and asbestinin-12 have been completed. A glycolate aldol reaction provided a diene useful for ring-closing metathesis to form an oxonene, which was ultimately employed as a template to execute a highly stereoselective intramolecular Diels-Alder cycloaddition, forming the hydroisobenzofuran moiety. The absolute configuration of the asbestinin subclass was confirmed via these synthetic efforts.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of familial and sporadic Parkinson's disease (PD). That the most prevalent mutation, G2019S, leads to increased kinase activity has led to a concerted effort to identify LRRK2 kinase inhibitors as a potential disease-modifying therapy for PD. An internal medicinal chemistry effort identified several potent and highly selective compounds with favorable drug-like properties. Here, we characterize the pharmacological properties of cis-2,6-dimethyl-4-(6-(5-(1-methylcyclopropoxy)-1H-indazol-3-yl)pyrimidin-4-yl)morpholine (MLi-2), a structurally novel, highly potent, and selective LRRK2 kinase inhibitor with central nervous system activity. MLi-2 exhibits exceptional potency in a purified LRRK2 kinase assay in vitro (IC50 = 0.76 nM), a cellular assay monitoring dephosphorylation of LRRK2 pSer935 LRRK2 (IC50 = 1.4 nM), and a radioligand competition binding assay (IC50 = 3.4 nM). MLi-2 has greater than 295-fold selectivity for over 300 kinases in addition to a diverse panel of receptors and ion channels. Acute oral and subchronic dosing in MLi-2 mice resulted in dose-dependent central and peripheral target inhibition over a 24-hour period as measured by dephosphorylation of pSer935 LRRK2. Treatment of MitoPark mice with MLi-2 was well tolerated over a 15-week period at brain and plasma exposures >100× the in vivo plasma IC50 for LRRK2 kinase inhibition as measured by pSer935 dephosphorylation. Morphologic changes in the lung, consistent with enlarged type II pneumocytes, were observed in MLi-2-treated MitoPark mice. These data demonstrate the suitability of MLi-2 as a compound to explore LRRK2 biology in cellular and animal models.

Development of a series of highly kinome-selective spleen tyrosine kinase (Syk) inhibitors with favorable druglike properties is described. Early leads were discovered through X-ray crystallographic analysis, and a systematic survey of cores within a selected chemical space focused on ligand binding efficiency. Attenuation of hERG ion channel activity inherent within the initial chemotype was guided through modulation of physicochemical properties including log D, PSA, and pKa. PSA proved most effective for prospective compound design. Further profiling of an advanced compound revealed bacterial mutagenicity in the Ames test using TA97a Salmonella strain, and subsequent study demonstrated that this mutagenicity was pervasive throughout the series. Identification of intercalation as a likely mechanism for the mutagenicity-enabled modification of the core scaffold. Implementation of a DNA binding assay as a prescreen and models in DNA allowed resolution of the mutagenicity risk, affording molecules with favorable potency, selectivity, pharmacokinetic, and off-target profiles.

While the immune system is essential for the maintenance of the homeostasis, health and survival of humans, aberrant immune responses can lead to chronic inflammatory and autoimmune disorders. Pharmacological modulation of drug targets in the immune system to ameliorate disease also carry a risk of immunosuppression that could lead to adverse outcomes. Therefore, it is important to understand the 'immune fingerprint' of novel therapeutics as they relate to current and, clinically used immunological therapies to better understand their potential therapeutic benefit as well as immunosuppressive ability that might lead to adverse events such as infection risks and cancer. Since the mechanistic investigation of pharmacological modulators in a drug discovery setting is largely compound- and mechanism-centric but not comprehensive in terms of immune system impact, we developed a human tissue based functional assay platform to evaluate the impact of pharmacological modulators on a range of innate and adaptive immune functions. Here, we demonstrate that it is possible to generate a qualitative and quantitative immune system impact of pharmacological modulators, which might help better understand and predict the benefit-risk profiles of these compounds in the treatment of immune disorders.

The combination of a hetero-Diels–Alder reaction of a N–N or N–O heterodienophile and 1,3-cyclopentadiene with ruthenium catalyzed ring-opening cross metathesis (ROCM) produces new functionalized heterocyclic five-membered rings. The cycloadduct of 1,3-cyclopentadiene and diethyl azidodicarboxylate underwent ROCM to give a 2.5:1 (E:Z) mixture of diastereomeric cyclic hydrazines. This substrate also appears to be a suitable precursor for ring-opening polymerization. The cycloadduct of 1,3-cyclopentadiene and an acyl nitroso compound underwent ROCM to give a mixture of four cyclic hydroxylamines. These results represent the first examples of ROCM on strained cyclic substrates containing multiple heteroatoms.

The aza-Cope-Mannich reaction and ring-closing metathesis are key steps in the assembly of intermediates containing rings A−D of Daphniphyllum alkaloids of the daphnicyclidin type such as daphnipaxinin and oldhamine A.

Brevetoxin A is a decacyclic ladder toxin that possesses 5-, 6-, 7-, 8-, and 9-membered oxacycles, as well as 22 tetrahedral stereocenters. Herein, we describe a unified approach to the B, E, G, and J rings based upon a ring-closing metathesis strategy from the corresponding dienes. The enolate technologies developed in our laboratory allowed access to the precursor acyclic dienes for the B, E, and G medium-ring ethers. The strategies developed for the syntheses of these four monocycles ultimately provided multigram quantities of each of the rings, supporting our efforts toward the completion of a convergent synthesis of brevetoxin A.

A highly convergent, enantioselective total synthesis of brevetoxin A is reported. The development of a [X + 2 + X] Horner–Wadsworth–Emmons/cyclodehydration/reductive etherification convergent coupling strategy allowed for a unified approach to the synthesis of two advanced tetracyclic fragments from four cyclic ether subunits. The Horner–Wittig coupling of the two tetracyclic fragments provided substrates that were explored for reductive etherification, the success of which delivered a late-stage tetraol intermediate. The tetraol was converted to the natural product through an expeditious selective oxidative process, followed by methylenation.

A highly convergent, enantioselective total synthesis of brevetoxin A is reported. The development of a [X + 2 + X] Horner–Wadsworth–Emmons/cyclodehydration/reductive etherification convergent coupling strategy allowed for a unified approach to the synthesis of two advanced tetracyclic fragments from four cyclic ether subunits. The Horner–Wittig coupling of the two tetracyclic fragments provided substrates that were explored for reductive etherification, the success of which delivered a late-stage tetraol intermediate. The tetraol was converted to the natural product through an expeditious selective oxidative process, followed by methylenation.

The C2-C11 cyclized cembranoids, which include the eunicellins (also known as the cladiellins), briarellins, asbestinins, and sarcodictyins, are secondary metabolites isolated from gorgonian octocorals and soft corals. An unusual oxatricyclic ring system containing a hydroisobenzofuran and an oxonene unit with stereogenic centers residing at C1-3, 9, 10, and 14 is common to the eunicellins, briarellins, and asbestinins. However, the location of the cyclohexyl methyl groups (C11 versus C12) and the oxidation level of the sixand nine-membered rings differ among the three classes. Faulkner has proposed that the cyclization of the cembranoid diterpene skeleton initiates a biosynthetic pathway that leads to all four subclasses of these unusual molecules (Figure 1). Beginning with the cembrane skeleton, C2-C11 cyclization provides the cladiellin framework. An intramolecular etherification of the cladiellin tricycle affords the tetracyclic framework of the briarellin subclass, and a subsequent 1,2-suprafacial methyl shift of the briarellin structure is postulated to deliver the asbestinins as the class that is furthest evolved from the cembrane skeleton. The presence of multiple structural types in a common organism provides circumstantial evidence for Faulkner’s proposed biosynthetic pathway. The isolation of a cembrane metabolite with cladiellin metabolites in Alcyonium molle and with asbestinin metabolites in Briareum steckii are specific examples. The sarcodictyins are also proposed to arise from a C2-C11 cyclization of the cembrane skeleton; however, in these systems, the cyclization results in a fused cyclohexane and oxonane in place of the hydroisobenzofuran of the cladiellins, briarellins, and asbestinins. As a result of this significant structural variation of the sarcodictyins, the synthetic approaches to these molecules are quite different than those for the other three related subclasses. This review will cover efforts toward the eunicellins, briarellins, and asbestinins but will not cover efforts toward the total synthesis of the sarcodictyins. Eunicellin was the first reported member of the C2-C11 cyclized cembranoid natural products, isolated in 1968 by Djerassi and co-workers from the soft coral Eunicella stricta found off the coast of Banyuls-sur-Mer in France. Since this discovery, over 100 unique secondary metabolites of gorgonian octocorals have been characterized, including the first asbestinin in 1980 and the first briarellin in 1995. A wide range of structural diversity is displayed by this group of marine natural products. The natural role of these cembranoids is proposed, based upon mollusk and fish lethality assays, to involve predation deterrence. Upon further investigation, several of the members of these subclasses have demonstrated significant pharmacological potential. Particularly, these diterpenes have been shown to exhibit in vitro cytotoxicity against various cancer cell lines, anti-inflammatory properties, antimicrobial activities, and histamine and acetylcholine antagonism. The fascinating molecular architecture of these cembranoids, as well as their potential as therapeutic agents, has sparked much interest in the synthetic community over the past decade. A variety of approaches toward these challenging structural motifs have been investigated and several total syntheses have been accomplished. Efforts toward the total synthesis of the cladiellins, briarellins, and asbestinins are the subject of this review.

A new synthesis of 3,3′-bioxindoles is reported that is well suited for the preparation of unsymmetrical structures. In the key step, 3-hydroxy-3,3′-bioxindoles are constructed by Mukaiyama aldol reaction of 2-siloxyindoles with isatins These tertiary carb inols are formed in high diastereoselectivities, with substitution at various positions of the isatin and the 2-siloxyindole being tolerated.

A total synthesis of brevetoxin A is reported. Two tetracyclic coupling partners, prepared from previously reported advanced fragments, were effectively united via a Horner—Wittig olefination. The resulting octacycle was progressed to substrates that were explored for reductive etherification, the success of which led to a penultimate tetraol intermediate. The tetraol was converted to the natural product through an expeditious selective oxidative process, followed by methylenation.

A new synthesis of 3,3′-bioxindoles is reported that is well suited for the preparation of unsymmetrical structures. In the key step, 3-hydroxy-3,3′-bioxindoles are constructed by Mukaiyama aldol reaction of 2-siloxyindoles with isatins These tertiary carb inols are formed in high diastereoselectivities, with substitution at various positions of the isatin and the 2-siloxyindole being tolerated.

A second-generation synthesis of the BCDE fragment of brevetoxin A is described. Novel reactions were developed that extend the utility of the asymmetric glycolate alkylation reaction and improve scale-up to provide gram quantities of the B and E subunits. Significant improvements to the convergent assembly of the tetracycle were also realized. In addition, formation of the A ring lactone was accomplished to complete the ABCDE pentacycle.

A highly stereoselective synthesis of 11-acetoxy-4-deoxyasbestinin D (1) has been completed in 26 linear steps. The synthesis hinges on a selective glycolate aldol addition to establish the C-2 stereocenter, a ring-closing metathesis reaction to complete the oxonene, and an intramolecular Diels−Alder cycloaddition to establish the relative configuration at C-1, C-10, and C-14. This initial total synthesis of an asbestinin also serves to confirm the absolute configuration of this subclass of the C-2−C-11-cyclized cembranoid natural products.

Simple harmonic motions of a vibrating surface can be decomposed into two component motions: a standing wave, which corresponds to a characteristic mode shape, and a traveling wave, which is associated with the flow of power along the surface. Random motions of the vibrating surface can be decomposed into a series of simple harmonic motions, each of which can be decomposed into standing and traveling components. Holographic measurement of the pressure field around an immersed, point excited, vibrating cylinder have been processed to reveal the series of standing and traveling waves noted above. The results have been visualized in computer‐generated movies and used to diagnose the structural response of the cylinder and power flow along and out of its surface. In this talk, the measurement, processing, and graphic display systems used to perform the diagnosis and features revealed by the investigation will be described.

Large vessels, such as ships and submarines, present unique challenges to designers of acoustic imaging systems. The measurement environment is usually noisy and reverberent. Acoustic data must be collected rapidly over large areas. Data processing systems need to be small, fast, and portable. Displays of the processed data must be appropriate for easily answering structural acoustics questions such as: What is the distribution of vibrations on a hull? Are the vibrations localized or distributed over a large area? Are modes coupled? Do the modes radiate? What is the distribution of acoustic energy in frequency and wave number as well as position? A multichannel acoustic imaging system has been developed and used to investigate a variety of structural acoustics problems associated with large underwater structures during the past year. In this talk, the imaging system used in these investigations will be described, examples of structural acoustics problems where the system has been found to provide importan...