Acc. Chem. Res.
 2015
DOI: 10.1021/ar500400w
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Total Synthesis of Vinblastine, Related Natural Products, and Key Analogues and Development of Inspired Methodology Suitable for the Systematic Study of Their Structure–Function Properties

Justin E. Sears
1
,
Dale L. Boger
2

Abstract: Conspectus Biologically active natural products composed of fascinatingly complex structures are often regarded as not amenable to traditional systematic structure–function studies enlisted in medicinal chemistry for the optimization of their properties beyond what might be accomplished by semi-synthetic modification. Herein, we summarize our recent studies on the Vinca alkaloids vinblastine and vincristine, often considered as prototypical members of such natural products, that not only inspired the developme… Show more

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Cited by 199 publications

(136 citation statements)
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“…After an extensive evaluation of a combination of bases and oxidants, it was found that generation of the lactam enolate of (−)-18 with LDA, trapping by (TMSO) 2 19,20 as the electrophilic oxidant, and in situ quench of the reaction directly without workup with TBSOTf/ pyridine provided (−)-19 (48%) as a single diastereomer ( 1 H NMR) (Scheme 3). In accord with our previous studies, 21,22 premixing (TMSO) 2 with (−)-18 prior to the addition of LDA at −40 °C was necessary to provide appreciable conversion in this transformation, whereas the conventional procedure of initial lactam enolate generation with LDA followed by addition of (TMSO) 2 only resulted in recovered starting material. Replacing LDA with the sterically more demanding NaHMDS, an alternative base implemented in combination with (TMSO) 2 , did not provide C11 oxidation, presumably failing to effect deprotonation.…”
Section: ■ Introductionsupporting
confidence: 85%
Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.
show abstract
“…After an extensive evaluation of a combination of bases and oxidants, it was found that generation of the lactam enolate of (−)-18 with LDA, trapping by (TMSO) 2 19,20 as the electrophilic oxidant, and in situ quench of the reaction directly without workup with TBSOTf/ pyridine provided (−)-19 (48%) as a single diastereomer ( 1 H NMR) (Scheme 3). In accord with our previous studies, 21,22 premixing (TMSO) 2 with (−)-18 prior to the addition of LDA at −40 °C was necessary to provide appreciable conversion in this transformation, whereas the conventional procedure of initial lactam enolate generation with LDA followed by addition of (TMSO) 2 only resulted in recovered starting material. Replacing LDA with the sterically more demanding NaHMDS, an alternative base implemented in combination with (TMSO) 2 , did not provide C11 oxidation, presumably failing to effect deprotonation.…”
Section: ■ Introductionsupporting
confidence: 85%
Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.
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“…The use of other conventional solvents, including CH 2 Cl 2 , CH 3 CN, MeOH, THF, and DMF, failed to produce 6a (entry 7). Similarly, the use of FeCl 3 instead of BAHA did not produce the product in meaningful amounts (not shown). Finally, the tertiary amine Et 3 N was more suitable relative than other organic or inorganic bases examined, and the addition of Lewis acids proved detrimental to the reaction (entries 8–15).…”
Section: Resultsmentioning
confidence: 91%
Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.
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“…In addition, as an important structural unit, indoline was widely used in fields such as pharmaceuticals and dyes. [ 16 ] In order to evaluate the universality of this method, a series of reactions using 1‐(pyrimidin‐2‐yl) indoline 4 and 2‐methylidene cyclic carbonate 2a were screened under optimal reaction conditions (Table 3). We obtained 5a in 60% yield.…”
Section: Resultsmentioning
confidence: 99%
Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.
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