Total synthesis of merrilactone a: Long-range stereocontrol and asymmetric desymmetrization

Masayuki Inoue, Takaaki Satou, Masahiro Hirama

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

( - )-Merrilactone A [( - )-l], isolated from Illicium merrillianum in 2000, possesses neunte outgrowth activity in cultures of fetal rat cortical neurons, and, therefore, is expected to show therapeutic potential for the treatment of neurodegeneration associated with Alzheimer's and Parkinson's diseases. Apart from its biological aspects, the caged pentacyclic skeleton of 1 poses interesting synthetic challenges. In this account, we describe the total synthesis of (+)- and ( - )-merrilactone A, based on two novel strategies. Both strategies employed, as a key step, a transannular aldol reaction of eight membered diketone to construct the core cis-bicyclo[3.3.0]octyl system of 1. In the first generation total synthesis, the 2,6bis(trifluoromethyl)benzyl group served as a long-range Stereocontrolling element for synthesis of the enantiopure bicyclo[3.3.0]octane framework of ( - )-l. On the other hand, asymmetric aldol reaction was developed in the second generation synthesis to build the fused core of (+)-l in a more consice manner. The obtained key intermediates were utilized as a platform for the subsequent functional group manipulations necessary for construction of ( - )- and (+)-l. Surprisingly, both the natural and unnatural enantiomers of 1 equally promoted neurite outgrowth in primary neuronal cultures.

Original languageEnglish
Pages (from-to)419-428
Number of pages10
JournalYuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry
Volume65
Issue number5
Publication statusPublished - 2007 May
Externally publishedYes

Fingerprint

Enantiomers
Functional groups
Neurons
Rats
3-hydroxybutanal
merrilactone A
octane

Keywords

  • Asymmetric desymmetrization
  • Conformational analysis
  • Long-range stereocontrol
  • Merrilactone A
  • Meso compound
  • Neurotrophic factor
  • Pairwise symmetrical functionalization
  • Radical reaction
  • Sesquiterpenoid
  • Transannular aldol reaction

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Total synthesis of merrilactone a : Long-range stereocontrol and asymmetric desymmetrization. / Inoue, Masayuki; Satou, Takaaki; Hirama, Masahiro.

In: Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry, Vol. 65, No. 5, 05.2007, p. 419-428.

Research output: Contribution to journalArticle

@article{ad18770ee5094e18be91325276be806a,
title = "Total synthesis of merrilactone a: Long-range stereocontrol and asymmetric desymmetrization",
abstract = "( - )-Merrilactone A [( - )-l], isolated from Illicium merrillianum in 2000, possesses neunte outgrowth activity in cultures of fetal rat cortical neurons, and, therefore, is expected to show therapeutic potential for the treatment of neurodegeneration associated with Alzheimer's and Parkinson's diseases. Apart from its biological aspects, the caged pentacyclic skeleton of 1 poses interesting synthetic challenges. In this account, we describe the total synthesis of (+)- and ( - )-merrilactone A, based on two novel strategies. Both strategies employed, as a key step, a transannular aldol reaction of eight membered diketone to construct the core cis-bicyclo[3.3.0]octyl system of 1. In the first generation total synthesis, the 2,6bis(trifluoromethyl)benzyl group served as a long-range Stereocontrolling element for synthesis of the enantiopure bicyclo[3.3.0]octane framework of ( - )-l. On the other hand, asymmetric aldol reaction was developed in the second generation synthesis to build the fused core of (+)-l in a more consice manner. The obtained key intermediates were utilized as a platform for the subsequent functional group manipulations necessary for construction of ( - )- and (+)-l. Surprisingly, both the natural and unnatural enantiomers of 1 equally promoted neurite outgrowth in primary neuronal cultures.",
keywords = "Asymmetric desymmetrization, Conformational analysis, Long-range stereocontrol, Merrilactone A, Meso compound, Neurotrophic factor, Pairwise symmetrical functionalization, Radical reaction, Sesquiterpenoid, Transannular aldol reaction",
author = "Masayuki Inoue and Takaaki Satou and Masahiro Hirama",
year = "2007",
month = "5",
language = "English",
volume = "65",
pages = "419--428",
journal = "Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry",
issn = "0037-9980",
publisher = "Society of Synthetic Organic Chemistry",
number = "5",

}

TY - JOUR

T1 - Total synthesis of merrilactone a

T2 - Long-range stereocontrol and asymmetric desymmetrization

AU - Inoue, Masayuki

AU - Satou, Takaaki

AU - Hirama, Masahiro

PY - 2007/5

Y1 - 2007/5

N2 - ( - )-Merrilactone A [( - )-l], isolated from Illicium merrillianum in 2000, possesses neunte outgrowth activity in cultures of fetal rat cortical neurons, and, therefore, is expected to show therapeutic potential for the treatment of neurodegeneration associated with Alzheimer's and Parkinson's diseases. Apart from its biological aspects, the caged pentacyclic skeleton of 1 poses interesting synthetic challenges. In this account, we describe the total synthesis of (+)- and ( - )-merrilactone A, based on two novel strategies. Both strategies employed, as a key step, a transannular aldol reaction of eight membered diketone to construct the core cis-bicyclo[3.3.0]octyl system of 1. In the first generation total synthesis, the 2,6bis(trifluoromethyl)benzyl group served as a long-range Stereocontrolling element for synthesis of the enantiopure bicyclo[3.3.0]octane framework of ( - )-l. On the other hand, asymmetric aldol reaction was developed in the second generation synthesis to build the fused core of (+)-l in a more consice manner. The obtained key intermediates were utilized as a platform for the subsequent functional group manipulations necessary for construction of ( - )- and (+)-l. Surprisingly, both the natural and unnatural enantiomers of 1 equally promoted neurite outgrowth in primary neuronal cultures.

AB - ( - )-Merrilactone A [( - )-l], isolated from Illicium merrillianum in 2000, possesses neunte outgrowth activity in cultures of fetal rat cortical neurons, and, therefore, is expected to show therapeutic potential for the treatment of neurodegeneration associated with Alzheimer's and Parkinson's diseases. Apart from its biological aspects, the caged pentacyclic skeleton of 1 poses interesting synthetic challenges. In this account, we describe the total synthesis of (+)- and ( - )-merrilactone A, based on two novel strategies. Both strategies employed, as a key step, a transannular aldol reaction of eight membered diketone to construct the core cis-bicyclo[3.3.0]octyl system of 1. In the first generation total synthesis, the 2,6bis(trifluoromethyl)benzyl group served as a long-range Stereocontrolling element for synthesis of the enantiopure bicyclo[3.3.0]octane framework of ( - )-l. On the other hand, asymmetric aldol reaction was developed in the second generation synthesis to build the fused core of (+)-l in a more consice manner. The obtained key intermediates were utilized as a platform for the subsequent functional group manipulations necessary for construction of ( - )- and (+)-l. Surprisingly, both the natural and unnatural enantiomers of 1 equally promoted neurite outgrowth in primary neuronal cultures.

KW - Asymmetric desymmetrization

KW - Conformational analysis

KW - Long-range stereocontrol

KW - Merrilactone A

KW - Meso compound

KW - Neurotrophic factor

KW - Pairwise symmetrical functionalization

KW - Radical reaction

KW - Sesquiterpenoid

KW - Transannular aldol reaction

UR - http://www.scopus.com/inward/record.url?scp=34547485459&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34547485459&partnerID=8YFLogxK

M3 - Article

AN - SCOPUS:34547485459

VL - 65

SP - 419

EP - 428

JO - Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry

JF - Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry

SN - 0037-9980

IS - 5

ER -