Enantioselective Total Synthesis of Macrolide Antitumor Agent (−)-Lasonolide A

Ghosh, Arun K.; Gong, Gangli

doi:10.1021/ol0701013

Cited by 52 publications

(35 citation statements)

References 32 publications

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“…Macrolactone 139 was prepared by intramolecular Horner-Emmons reaction. This was converted to lasonolide A ( 22 ) 29. Using synthetic lasonolide A, we have investigated the biological mechanism of action in collaboration with Dr. Yves Pommier of the National Cancer Institute.…”

Section: Introductionmentioning

confidence: 99%

Capturing the Essence of Organic Synthesis: From Bioactive Natural Products to Designed Molecules in Today’s Medicine

Ghosh

2010

J. Org. Chem.

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In this perspective article, I outline my group's research involving the chemical syntheses of medicinally important natural products, exploration of their bioactivity, and development of new asymmetric carbon-carbon bond forming reactions. The article also highlights our approach to molecular design and synthesis of conceptually novel inhibitors against target proteins involved in the pathogenesis human diseases, including AIDS and Alzheimer's disease.

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Section: Introductionmentioning

confidence: 99%

Capturing the Essence of Organic Synthesis: From Bioactive Natural Products to Designed Molecules in Today’s Medicine

Ghosh

2010

J. Org. Chem.

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“…12 DIBAL-H reduction of ester 4 provided aldehyde 5, which was condensed with nitrobutane to afford nitroalkene 6 using a two-step procedure. 13 Zinc-mediated reduction 14 afforded the oxime 7, and subsequent NaCNBH 3 reduction 8b afforded a 1:1 inseparable mixture 1a and 1b). Importantly, the lack of stereocontrol at C2 resulting from this reduction offered the opportunity to study the cyclization of both epimers.…”

Section: Methodsmentioning

confidence: 99%

Synthesis of 2-epi-Pumiliotoxin C via a Challenging Intramolecular Hydroamination Key Step

Lebrun¹,

Pfeiffer²,

Beauchemin³

2009

Synlett

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The synthesis of 2-epi-pumiliotoxin C was achieved in ten steps from cyclohexadiene oxide, using a challenging Cope-type hydroamination key step. This cyclization was performed on a mixture of two epimeric hydroxylamines, and a boat transition state is proposed to explain the kinetic preference observed for the cyclization of the epimer leading to N-hydroxy-epipumiliotoxin C.Saturated, six-membered nitrogen heterocycles are present in a variety of natural products and medicinally important compounds. Diverse synthetic strategies and methods have been developed to access such motifs, and a variety of general, broadly applicable approaches have emerged. Strategies that involve formation of the heterocyclic ring system include cycloadditions, reductive aminations, iminium-based cyclizations, and ring-closing metathesis (to name a few). Intramolecular hydroaminations also hold the potential to be broadly applicable: 1 the cyclization can occur via formation of the C-N bond between a nitrogen atom and an unsaturated precursor (alkyne, allene, diene, or alkene) and stereoselective variants are possible. 2 However, hydroamination remains an underutilized synthetic strategy in heterocyclic synthesis (Scheme 1). 3 Scheme 1Reported examples of six-membered ring formation via intramolecular alkene hydroamination are especially rare. Most of these examples feature the use of transition-metal catalysts and require terminal alkenes, 4 and it is well established that increased alkene substitution, especially at the distal position (R 2 = H), usually results in significantly decreased hydroamination reactivity. 5 From a synthetic standpoint, such hydroaminations are desirable and could offer a unified approach for the synthesis of various alkaloid families, including 2-alkylpiperidines, benzyl tetrahydroisoquines, and b-carbolines. As such, synthetic efforts addressing this critical requirement for distal alkene substitution in six-membered ring-forming intramolecular hydroaminations are needed. 5 Herein, we report such synthetic studies in the pumiliotoxin C system that resulted in the synthesis of 2-epi-pumilitoxin C (Scheme 2). 6 Scheme 2In line with our current efforts focusing on Cope-type hydroaminations as a concerted, thermal alternative to the use of transition-metal catalysis, 7,8 we selected hydroxylamine 1b (R = OH) as the desired cyclization precursor. Since six-membered forming Cope-House cyclizations have mostly been reported on terminal alkenes (Scheme 3), 9 difficult cyclization was expected. However, based on our intermolecular studies that highlighted the importance of the proton-transfer step of the N-oxide intermediate to the hydroxylamine, 7a we speculated that protic solvents could provide increased efficiency in Cope-House cyclizations, and allow this difficult cyclization despite the distal alkene substituent present in 1. Scheme 3

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“…This endeavor resulted in the total synthesis of numerous targets, covering over two dozen or so different structural families. Some notable examples of our accomplished bioactive targets include novel and exceedingly potent microtubule stabilizing agents, laulimalide ( 1 )4 and peloruside A ( 2 )5 a potent microtubule destabilizing agent cryptophycin 52 ( 3 )6; anticancer agents amphidinolide T ( 4 )7, amphidinolide W ( 5 )8, and lasonolide A ( 6 )9; antibiotic agent, madumycin II ( 7 )10; pancreatic lipase inhibitor, tetrahydrolipstatin ( 8 )11; novel actin inhibitory agents doliculide ( 9 )12 and jasplakinolide ( 10 )13; novel antibacterial agent platensimycin ( 11 )14; and the histone deacytelase inhibitor, largazole ( 12 )15 (see Figure 1). The unique structural features of these natural products required the development of new synthetic tools and methodologies for their synthesis.…”

Section: Introductionmentioning

confidence: 99%

Enantioselective Total Synthesis of Macrolide Antitumor Agent (−)-Lasonolide A

Cited by 52 publications

References 32 publications

Capturing the Essence of Organic Synthesis: From Bioactive Natural Products to Designed Molecules in Today’s Medicine

Capturing the Essence of Organic Synthesis: From Bioactive Natural Products to Designed Molecules in Today’s Medicine

Synthesis of 2-epi-Pumiliotoxin C via a Challenging Intramolecular Hydroamination Key Step

Harnessing Nature’s Insight: Design of Aspartyl Protease Inhibitors from Treatment of Drug-Resistant HIV to Alzheimer’s Disease

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