H30：様式甲／Style Kou ２－１
学位論文の要旨
Abstract of Thesis 研究科
School
自然科学研究科
専 攻
Division 地球生命物質科学専攻
学生番号
Student No.
51428203
氏 名
Name
Andreas Meissner
学位論文題目 Title of Thesis（学位論文題目が英語の場合は和訳を付記）
Study of the Convergent Synthesis of Enigmazole A, Neopeltolide and Ciguatoxin 3C
(Enigmazole A、Neopeltolide及びCiguatoxin 3Cの収束的合成についての研究) 学位論文の要旨 Abstract of Thesis
This thesis consists of two parts. In the first part, synthetic studies of the two macrolides enigmazole A and neopeltolide are described. Enigmazole A was isolated from the marine sponge cinachyrella enigmatica and gained much interest due to its strong cytotoxicity and complex structure, resulting in five total syntheses to date. The synthesis presented in this thesis started from ethyl bromopyruvate I and chiral propargylic alcohol II. Following a literature procedure, dithiane III was prepared and coupled to chiral epoxide IV to give chiral alcohol V which was converted to the carboxylic acid fragment VI. Esterification of VI with alcohol fragment VII under Shiina conditions furnished ester VIII.
Reductive acetylation of the ester VIII gave α-acetoxy ether IX. The cyclization precursor IX was subjected to the intramolecular allylation with MgBr2·OEt2 to provide THP derivative IX was prepared and converted to lactone X by Yamaguchi`s conditions. Selective deprotection of the MOM group delivered alcohol XI, a known synthetic intermediate of enigmazole A XII.
OH
Me EtO
O
O Br
H S S
O
N Me
OMe
Me TBSO
O
S S
O
N Me
OMe Me TBSO
HO
O
N Me
OMe Me HO2C
MPMO OTBS
carboxylic acid fragment (VI)
OMOM
Me Me OTBS
alcohol fragment (VII)
O O OMOM
Me Me OTBS OTBS
O O
N Me
OMe Me
MPM TMS
OH TMS
I
II
III
IV
V
VIII
H30：様式甲／Style Kou ２－２ Name Andreas Meissner
O O
Me Me O O
OH O
N Me
OMe Me HO P
HO O
Enigmazole A (XII) Literature
DIBAL
then(ClCH2CO)2O
O OH
Me Me O
O O
N Me
OMe Me
MPM O
IX X
XI
O OMOM
Me Me OTBS OTBS
O O
N Me
OMe Me
MPM MgBr2
⋅OEt2
O O OMOM
Me Me OTBS OTBS
O O
N Me
OMe Me
MPM TMS
Cl O
VIII
Next, the synthesis of the macrolactone core of neopeltolide, isolated from the marine sponge of Daedalopelta is described. Since its isolation, neopeltolide became a quite famous target for synthetic chemists. To date, more than 20 formal and total syntheses are published. Using L-aspartic acid XIII as the starting material, alcohol XIV was prepared according to a literature procedure. Subjection to a reaction sequence involving chiral allylation gave lactone XV. Further transformation led to the carboxylic acid fragment XVI. The acid was coupled to alcohol fragment XVII under Shiina`s conditions to give ester XVIII. Reductive acetylation and intramolecular allylation installed the desired THP ring of derivative XIX. This compound was transformed to the macrolactone XX which is a known synthetic intermediate of neopeltolide XXI.
The second part of this thesis discusses research towards the polyether ciguatoxin 3C, isolated from the dinoflagellate Gambierdiscus toxicus. Two syntheses are published from Hirama`s group which gave fundamental insights in the reactivity of the protecting groups. The synthetic study was based on H-M ring fragment XXII. The stannane containing acetal was prepared via reductive acetylation and acetal exchange to give XXIII. Conversion to
OH O
O HO
NH2
O
O Me
OH
O
O Me
OTBDPS Me
Me
TBDPSO OMeMe O OH
carboxylic acid fragment (XVI)
TMS OH
TBSO
Me TBDPSO
Me
OMe O
O TBSO
Me TBDPSO
OMe Me O TBSO
TMS
reductive acetylation intramolecular allylation
Me O O O
O
Me OMe
O N
O NH
OMe O Me
O O O
Me OMe
O
Literature alcohol fragment (XVII)
L-aspartic acid (XIII)
XIV XV
XVIII XIX
XX
Neopeltolide (XXI)
H30：様式甲／Style Kou ２－３ Name Andreas Meissner
the carboxylic acid fragment XXIV and coupling to A-E alcohol fragment XXV under Shiina`s conditions delivered ester XXVI. Treatment with TMSI/HMDI furnished an allyl stannane which was subjected to reductive acetylation and intramolecular allylation to install the desired G-ring of compound XXVII.
O O
O O
O O
O H H
H H
H Me ONAPMe H
Me H
H
H Me
ONAP O
O
O O
O O
OH H H H H
ONAP
H H H H H
TBDPSO
Me SnBu3
O
O O
O O
O H H
H H
H Me
Me H Me
H H
H Me
ONAP O
O
O O
OH H H H H
ONAP
H H H H H
TBDPSO
Me O
ONAP
H O
H TMSO
O O
O
O O
O H H
H H
H Me ONAPMe H
Me H
H
H Me
ONAP TBSO
Me
O O
O O
O O
O
H H H
H H Me ONAPMe H
Me H
H
H Me
ONAP TBSO
MeO
SnBu3
Me
HO2C O
O
O O
O O
O
H H H
H H Me ONAPMe H
Me H
H
H Me
ONAP MeO
SnBu3
Me carboxylic acid fragment (XXIV)
alcohol fragment (XXV) OH O O
O O
OH H H H H
ONAP
H H H H H
TBDPSO
reductive acetylation intramolecular allylation
MeO
XXII XXIII
XXVI
XXVII
