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X tetrodotoxin X tagtitoxin

T FARI X

X

X X

X

X X

N

HN

OH

HOOHH2N

O

O

H

HOO

OH

tetrodotoxin (TTX) tagetitoxin

O

OPO3H-

S

COOH

+H3N

AcO

OHH2N

O

S

N

HO

N

S

COOH

HOO

5

OH

OH

H

HO

O

HHOHO

OHO

OHHO

HO

O

ouabainluciferin FARI

O

Onepetalactone

OO

O O

OO

OMe

oscillatoxin D (OTX-D)

OH

15

11

1

4

7

physalin Aa bitter principle of Physalis alkekengi

O

H

O OO

OOOH

O

HO

O

H

HOO

OHO chaxine Bsteroidal compound

fron an edible mushroom

HN

N NH

HN

O

H2NNH2

H2N

O

OHOH

HN

NH O

H2N

O

OMe 7

crambescin B COOH saxitoxin (STX)

NH

O

OH

O

OH

H

sespendole

NN

O

NH

NH2

NH2

peramine

p

6

h 6 m ( k

s e k X r a

R -D D k X ) R F

k k

k X i R k r a Q

6km h T R X k r Im k

6 k r

6

k k 6 R gL hR

X r aR k m rrg 6 R T

at k r R Qu Q

r k r k Q T 6

h R X o r Im

k p

r r

N

HN

OH

HO

OHH2N O

O

H

HO

5H

5-deoxyTTX (from puffer)

N

HN

OH

HOHH2N

OO

OHO

H OH

8-deoxyTTX(unnatural)

O

NH

O

COCCl3

common intermediate

HO OH

N

HN

OH

HOOHH2N

OO

OHO

OHH

tetrodotoxin (from puffer)

8

N

HN

OH

HOOHH2N

OO

OHO

COOOH

NH3

H

chiriquitoxin (from frog)

bromolevoglucosenone

O

O

O

H H

R Br

N

HN

CH3

OH

HOOHH2N

OO

OHO

H11

11-deoxyTTX (from puffer)

8N

HN

CH3

OH

OHH2N OO

OHO

H H11

8,11-dideoxyTTX(unnatural)

N

HN

CH3

OH

HOOHH2N O

O

H

HO

115H

5,6,11-trideoxyTTX (from puffer)

R = HR = OTBDPS

11

O

NH

O

COCCl3

5,11-dideoxyTTX(from newt)

N

HN

CH3

H

HOOHH2N O

O

H

HOH

Q X a 6 h

m 6 h h r R

Q k R 6k X R

X r a u X a m 6 R gL h

g Im 6k k 6

h k 6 t t r

k km h

a RL r k a o k g

X h u g Q g 6 R

Qm k k r r gm 6

g 6Ri k Q h r

2. tagtitoxin (Tgt)m 1981 k Pseudomonus syringase pv. Tagetis Q

X a g RAN RNAP

r Tgt m h k e RNAP RNAPIII

k ueat h r Q Tgt

m 1981 k X RX r R r k k

r gm hg k

r

rgk X a Tgt m

N

HN

OH

HOOHH2N

O

O

H

HOO

OH

tetrodotoxin (TTX)

N

HN

OH

HOOHH2N

O

H

HO

OH

OH

N

HNH2N

HOH

Cep-21010-hemiketal-TTX

S

COOHHO

OHCOOH

OPO3HH3N

AcO

HO O

S

H

OPO3H

HOOCCOOH

OH

H

NH NH3

AcO

NH3

HO3PO

HOOC H

S OHCONH2

OAc

201619891981

m k r

k k h n

hR r m (

k k X

h X r Q

R k µ

h R k Q i

r k QkX r gm

k r k k r h

t t r

k r

N

actinidine

O

O

O

OH

nepetalactolnepetalactone

O

O

iridomyrmecin

O

O

iso-iridomyrmecin

O

O

O

O

dihydronepetalactone

isodihydronepetalactone

PhNHMe

O

N HPh

CHO

O

H

(S)-citronellal

O

OH

O

H

dihydronepetalactone

h D 7A D m

h k r Q

Ri k Q T Q r g a Im

� 1 7 D7 3 h k

2Q t g 40 Q 9

Qk r a ra k 40

R h 40m T R

gL h Qk r a 40

h r

� 1 7 D7 3

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� i i Q m

s Q u eQ r m J Q eQ a

h g

.-2 h n r n Q R

Q eQ r ra R e

R a Q

R Q .-2 h X r Q .-2 m

E9 Q g at R h X au m Q QL r

.-2 TR Q eQ hm

hg Q Ri k .-2 Q h

g i T R r X r gm

.-2 r n .-2 h n

.-2 e

hg k hhuk T

h r �

�

( �

m h

R h k

h r 2 2

h n m TQ T

T X r a rgk

R Qk ra

Q i k R Qke

µ R Q r a Q

Ri k Q m k r r

u Qk r

gm h g k r

m gL hR Q h -

g g g R R

h 8 Q k

k h r

8

O

O

COOHH2N

HS+

S

N

HO S

N COOH

NH4OAcbuffer (30 °C, 3 h)

O2

0.30 ± 0.24 %

OH

H

HHO

19-norbufalin

HH

H

O

O

HO

HOOH

H

H

OH

proposed structure of Inagami-Tamura EDLF

OH x 2

OH

OH

H

HO

O

HHOHO

OH

ouabain

O

O

OHHO

HO

x x x x

x t x .

y va a r c

a r v tir r sy x w

w x x v

i l ts x irb i l s

sy x : t s x

x v x ptir

: x

w x

tir v y t

x x v tir r

px v or lx y r

th r sy x x w

x i px v w

i i

w x

x w or

HN

OO

O

CCl3[HO]

guanidine

carbamate

deprotection

site-selectivehydroxylation

N

HN

OH

HOOHH2N

OO

OHO

OHH

tetrodotoxin

isonitrile

HNHN

NHN

OH

NH2

HO

H2N

STX skeleton

A

C

HNN3

HO

NH2

CbzN

HN

NCbzN

N3

OBrBr

6

5

HN

NCbzN

HN

NHCbz

NCbz

OH

H

O

O

NBoc

OH

OTBS

O

NBoc CHO

HMPA

toluene-78 ºC

OTBS

Li

>10:1

OMs

Br+

B(TFA)3

THF

0 x w i a 1EII BANED x

s w x v

t wi i (

w 1 5 x

w x

x v x c x t 1 7

1P EJO E HER , LL, -

o w x

y x t

i t r i o

s a sw x w y t u

sy x x x o v

i w i i )

x

y w or h

s a w h

crambescin B carboxylic acid

HN

NH O

H2N

O

OMe

HN

NH O

CbzN

OAcMe

BrBr

HN

NH2CbzN

OAcMe

HO

N

TBDPSO

9

CbzNNHBoc

9

9MeO

HO

9Me

HO

9Me

9 PyHBr3 K2CO3

CH2Cl2-H2O

(73%)

(R,R)-salan ligand Ti(O-iPr)4, WXR

30% H2O2, CH2Cl2

3 steps

Pd(PPh3)4InI, formalin

4 steps

+3 steps

(i) N-alkynylation(ii) 6-endo cyclization

NNH2

O

R

NN

O

RH

NH HN

O

R

X3

NN

O

NH

NH2

NH2

peramine

v or sy t

w w w s

x w i C KNN CKPLIHJF t o

w or 01 t s

x

( x t .

. 0 1 ASHJE 0 tlx y w

or F KCTBE C ASHJFP h

s 0 a h r t 12 a ir w x

v v or x

x ta h i a gc i

v lx y wvor

w x

NH

O

OH

O

OH

H

sespendole

A BC D

E31

OTBS

OTMS

H

NO2

O

OHOTf

HO

+NH2

O

OH

O

OH

HOR

NO2

OHC OH

O

OE

D

Wieland-Miescher's ketone

cascadereaction

Sonogashiracoupling

aromatic segment terpene segment

E

DE

D

A A

A

12 steps 23 steps

OH

RH

H

OH

RH

H

tachysterol

O

H

HOO

OHO

H

HHO

ergosterol

OO

O

RH

HOO

OH

chaxine B(revised structure)

OH

RH

HOhv (254 nm)OO

WX-R/CH2Cl2

1) DBU CH2Cl2

2) TMSOTf AW-300 CH2Cl2

MCPBA

OO

CH2Cl2

silica gel

1)

2)

1) TBHP VO(acac)2

2) silica gel

BB(revised structure)

O

H

HOO

OHO

sy x i lx w or

v i i x w or

i v tir x

vu ir

p o x x 66

x xt ( , LL

. 1

y h x s

x v y 1 81

x w ta wvor 2x y t u

r sy x ts

Xt h r v ir Xy

w rx a h t sw

1 2tlx x w ir ,

x

) x x

w h wy tir

s v or xndsvc x v x

tir h r x wy

v t v e DE JK K

x a sy v

OO

O O H

OHO

OH

Me O

OMe

aplysiatoxin (ATX)

OO

O O

OR

O

OMe

oscillatoxin D

30

15

111

4

7

O

OMe

O

O

O

OMe

common intermediate

CHO

OMe

MgBr

14 steps

R

HO

HO

HO

Br

ORO

OO O

Me

OH2

OR

HO

RO O

w x DE JK K w d x o i

i - y rx w x tv

ir p

x a s w or x 3294 x

i i tir

x i

y p x

2 6 t w

1 Nishikawa, T.; Urabe, D.; Adachi, D.; Isobe, M. Synlett 2015, 26, 1930-1939. 2 Nishikawa, T.; Isobe, M. Chem. Rec. 2013, 13, 286-302. DOI: 10.1002/tcr.201200025 3 (a) Sawayama, Y.; Nishikawa, T. Angew. Chem. Int. Ed. 2011, 50, 7176-7178. DOI:

10.1002/anie.201102494 (b) Ueno, S.; Nakazaki, A.; Nishikawa, T. Org. Lett. 2016, 18, 6368-6371, 2016. DOI: 10.1021/acs.orglett.6b03262

4 (a) Nakazaki, A.; Ishikawa, Y.; Sawayama, Y.; Yotsu-Yamashita, M.; Nishikawa, T. Org. Biomol. Chem. 2014, 12, 53-56. DOI: 10.1039/c3ob42017e (b) Nakazaki, A.; Nakane, Y.; Ishikawa, Y.; Yotsu-Yamashita, M.; Nishikawa, T. Org. Biomol. Chem. 2016, 14, 5304-5309. DOI: 10.1039/C6OB00914J (c) Tsukamoto, T.; Chiba, Y.; Nakazaki, A.; Ishikawa, Y.; Nakane, Y.; Cho, Y.; Nishikawa, T.; Yotsu-Yamashita, M.; Wakamori, M.; Konoki, K. Bioorg. Med. Chem. Lett. 2017, 27, 1247-1251. DOI: 10.1016/j.bmcl.2017.01.054

5 (a) Yamamoto, Y.; Nakazaki, A.; Nishikawa, T. Tetrahedron 2017, 73, 3443–3451. DOI: 10.1016/j.tet.2017.05.004. (b) Ito, S.; Yamamoto, Y.; Nishikawa, T. Biosci. Biotechnol. Biochem. 2018, 82, 2053-2058. (DOI: 10.1080/09168451.2018.1511966)

6 (a) Sugino, K.; Nakazaki, A.; Isobe, M.; Nishikawa, T. Synlett 2011, 647-650. DOI: 10.1055/s-0030-1259551 (b) Adachi, M.; Higuchi, K.; Thasana, N.; Yamada, H.; Nishikawa, T. Org. Lett. 2012, 14, 114-117. DOI: 10.1021/ol202895u (c) Ono, Y.; Nakazaki, A.; Ueki, K.; Higuchi, K.; Sriphana, U.; Adachi, M. Nishikawa, T. J. Org. Chem. 2019, 84, 9750-9757. DOI: 0.1021/acs.joc.9b01597

7 Hirata, Y.; Nakazaki, A.; Kawagishi, H.; Nishikawa, T. Org. Lett. 2017, 19, 560-563. DOI: 10.1021/acs.orglett.6b03724

8 Nokura, Y.; Araki, Y.; Nakazaki, A.; Nishikawa, T. Org. Lett. 2017, 19, 5992-5995. DOI: 10.1021/acs.orglett.7b03032

OH

OH

H

HO

O

HHOHO

OHO

OHHO

HO

ouabain(cardiotonic steroid)

O

HO

HOOH

H

H

OH

proposed structue of Inagami-Tamura EDLF

(estrogenic steroid)

OH x 2OH

OH

H

OH

HO

O

OH

OH

HO

O

OHOH

OH

OH

R

Mizoroki-Heckreaction

– CO2

R

H H

H

OH

H OH

OH

OO

H

estrogenic compound

cardiotonic steroidal compound

IMDAreaction

IntramolecularDiels-Alder (IMDA)

reaction

key intermediates

9 (a) Nakazaki, A.; Hashimoto, K.; Ikeda, A.; Shibata, T.; Nishikawa, T. J. Org. Chem. 2017, 82, 9097-9111.

DOI: 10.1021/acs.joc.7b01640 (b) Watanabe, S.; Nishikawa, T.; Nakazaki, A. Org. Lett. 2019, 21, 7410-7414. DOI: 10.1021/acs.orglett.9b02716

�&?+ 28

Synthetic Study on Lycojapodine A A

29

30

�&?+ 28

Inagami-Tamura EDLF ( )

A

29

Oscillatoxin D Aplysiatoxin

8

30

RCAI-56 α-

Pd 0

B

�-?+ 28

A

Crambescin

29

Plumisclerin A A

Chaxine 19-

30 A

petromyzestrosterol

CA 28 (JT))

) ) MST

29

30 ) )OAT ) ) ) )

%� +� (1) Bian, L.; Cao, S.; Cheng, L.; Nakazaki, A.; Nishikawa, T.; Qi, J. Semi-synthesis and

Structure-Activity Relationship of Neuritogenic Oleanene Derivatives. ChemMedChem 2018, 13, 1972-1977. (DOI: 10.1002/cmdc.201800352)

(2) Huang, Y.; Nishikawa, T.; Nakazaki, A. Toward a synthesis of fawcettimine-type Lycopodium alkaloids: stereocontrolled synthesis of a functionalized azaspirocycle precursor. J. Org. Chem. 2018, 83, 11108-11117. (DOI: 10.1021/acs.joc.8b01719)

(3) Qi, J.; Cheng, L.; Sun, Y.; Hirata, Y.; Ushida, N.; Ma, Z.; Osada, H.; Nishikawa, T.; Xiang. L. Identification of an Asexual Reproduction Inducer of Phytopathogenic and Toxigenic Fusarium. Angew. Chem. Int. Ed. 2018, 57, 8100-8104. (DOI: 10.1002/anie.201803329)

(4) Damnjanovic, J.; Matsunaga, N.; Adachi, M.; Nakano, H.; Iwasaki, Y. Facile Enzymatic Synthesis of Phosphatidylthreonine Using an Engineered Phospholipase D. Eur. J. Lipid Sci. Technol. 2018, 120, 1800089-1800095. (DOI: org/10.1002/ejlt.201800089)

(5) Ito, S.; Yamamoto, Y.; Nishikawa, T. A concise synthesis of peramine, a metabolite of endophytic fungi. Biosci. Biotechnol. Biochem. 2018, 82, 2053-2058. (DOI: 10.1080/09168451.2018.1511966)

(6) Adachi, M.; Miyasaka, T.; Kudo, Y.; Sugimoto, K.; Yotsu-Yamashita, M.; Nishikawa, T. Total Syntheses and Determination of Absolute Configurations of Cep-212 and Cep-210, Predicted Biosynthetic Intermediates of Tetrodotoxin Isolated from Toxic Newt. Org. Lett. 2019, 21, 780-784. (DOI: 10.1021/acs.orglett.8b04043)

���91�<�

(1) 8 vol.101 2018 3 pp45.

(2) 26 )

2018 pp104-107.

(3) 2 2 II - 2

- 64 2018 pp107-112.

(4) )

CSJ Current Review 272018 pp86-93.

!E�������4:

(1) D)30 6

2018.6.1-2018.6.2.

(2) (

113 2018 2018.6.6-2018.6.7.

(3) ) ) ) Aplysiatoxin 1132018 2018.6.6-2018.6.7.

(4) ) ) ) ) 113 2018.6.6-2018.6.7.

(5) 302018.6.30.

(6) ) α 2018.7.20.

(7) ) ) ) RCAI-56 α- 2018 2018.7.26-2018.7.27.

(8) C-N 2018.7.30.

(9) C-N 2018.7.31.

(10) 8

1 2018.8.16-2018.8.17.

(11) Masato Kasuga, Clyde Gorapava Puilingi, Atsuo Nakazaki, Shunsuke Tsunogae, Yuko Cho, Keiichi Konoki, Mari Yotsu-Yamashita: Screening for bioactive compounds in marine organisms collected in the Solomon Islands. Tohoku University's Chemistry Summer School 2018 (Sendai) 2018.8.27-2018.8.28.

(12) ) ) 2- 8 Diels-Alder

48 2018.9.3-2018.9.5.

(13) ) )

183 2018.9.15.

(14) ) ) ) ) ) Chaxine183 2018.9.15.

(15) ) ) ) ) ) ) Oscillatoxin D 60 2018.9.26-2018.9.28.

(16) ) ) ) ) ) ) ) )

) ) ) ) ) )

602018.9.26-2018.9.28.

(17) ) ) B 492018.11.3-2018.11.4.

(18) ) ) 19-norbufalin 49

2018.11.3-2018.11.4.

(19) Diels-Alder 8

2018.11.7-2018.11.8.

(20) 5 in2019.11.9.

(21) Toshio Nishikawa, Misaki Niki, Yushi Hirata, Atsuo Nakazaki, Hidenori Kawagishi : Collective Synthesis of Chaxines, Novel Steroidal Natural Products Isolated from Chinese Edible Mushroom. The 14th International Kyoto Conference on New Aspect of Organic Chemistry (Kyoto, Japan) 2018.11.12-2018.11.16.

(22) Yusuke Hanaki, Yusuke Araki, Yoshihiko Nokura, Atsuo Nakazaki, Masaki Kita, Kazuhiro Irie, Toshio Nishikawa: Synthetic studies on oscillatoxin D and its analogs. The 4th International Kyoto Conference on New Aspect of Organic Chemistry (Kyoto, Japan) 2018.11.12-2018.11.16.

(23) Toshio Nishikawa: Towards a Unified Synthesis of Aplysiatoxin and oscillatoxin Famile. The 4th International Symposium on Middle Molecular Strategy (ISMMS-4) 2018.11.30-2018.12.1.

(24) Yoshiki Nakane, Atsuo Nakazaki, Toshio Nishikawa: Synthetic Studies on chartelline C.

2018 2019.1.9.

(25) Yushi Hirata, Toshio Nishikawa: Synthetic studies on brachialactone, a novel nitrification inhibitor.

2018 2019.1.9.

(26) Yuuta Yamamoto, Toshio Nishikawa: Synthetic studies on conidiogenone, a strong conidiogenesis inducer of fungi.

2018 2019.1.9.

(27) Yusuke Araki, Toshio Nishikawa Synthetic Studies on Physalins 2018

2019.1.9. (28) Shogo Watanabe, Toshio Nishikawa, Atsuo Nakazaki: A new synthetic approach to cardiotonic st

eroids. 2018 2019.1.9.

(29) Tadaaki Tsukamoto, Yukie Chiba, Shunsuke Tsunogae, Tomoshi Yamada, Yuko Cho, Ryo Sakakibara,

Takuya Imazu, Shouta Tokoro, Yoshiki Satake, Yuki Ishikawa, Yoshiki Nakane, Masaatsu Adachi, Atsuo Nakazaki, Toshio Nishikawa, Minoru Wakamori, Mari Yotsu-Yamashita, Keiichi Konoki: Sensitivity of the voltage-gated sodium channel subtypes, Nav1.1 to Nav1.7, against guanidine-containing natural products and their analogues. The 1st International Symposium on Chemical Communication (ISCC2019) (Tokyo) 2019.1.9-2019.1.10.

(30) ) ) ) ) ) ) ) Oscillatoxin D 2019 2019.3.24-2019.3.27.

(31) ) ) Chartelline C 20192019.3.24-2019.3.27.

(32) ) ) ) ) ) 2019

2019.3.24-2019.3.27. (33) ) ) 2- Diels-Alder

2019 2019.3.24-2019.3.27.

(34) ) ) ) RCAI-56 α-2019 2019.3.24-2019.3.27.

(35) ) ) Pd 0

2019 2019.03.24-2019.03.27.

(36) ) ) ) B2019 2019.3.24-2019.3.27.

(37) ) ) ) ) ) Chaxine2019 2019.03.24-2019.03.27.

(38) ) ) 19- 2019

2019.3.24-2019.3.27.

(39) ) ) A2019 2019.3.24-2019.3.27.

(40) ) ) ) ) ) ) ) )

2019 2019.3.24-2019.3.27.

(41) )Clyde Gorapava Puilingi) ) ) ) ) )

Nav 20192019.3.24-2017.3.27.

(42) ) ) 20191

2019.3.24-2019.3.27.

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(4) 2019 . 2019.3.26.