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Ac: acetyl
AIBN: 2,2’-azobis(isobutyronitrile)
Bn: benzyl
Bu: butyln-: normalt-: tertiary(S)-BINAP: (S)- 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
CIMS: chemical ionization mass spectrometry
CuTC: copper(I)thiophene-2-carboxylate(S,S)-Chiraphos: (2S,3S)-(−)-bis(diphenylphosphino)butane
dba: dibenzylideneacetone
DDQ: 2,3-dichloro-5,6-dicyano-p-benzoquinone
DIPEA: N,N-diisopropylethylamine
DMA: N,N-dimethylacetamide
DMAP: N,N-dimethyl-4-aminopyridine
DME: dimethyl ether
DMF: N,N’-dimethylformamide
DMSO: dimethyl sulfoxide
Dppe: bis(diphenylphosphino)ethane
EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
EIMS: electron impact mass spectrometry
Et: ethyl
Grubbs II catalyst: Hoveyda-Grubbs catalyst 2nd generation
Me: methyl(R,R)-Me-BPE: (+)-1,2-bis[(2R,5R)-2,5-dimethylphospholano]ethane
MOMCl: chloromethyl methyl ether
Ms: methanesulfonyl(S)-MTPA: (S)-(−)-α-methoxy-α-(trifluoromethyl)phenylacetic Acid
(S)-(+)-MαNP acid: (S)-(+)-2-methoxy-2-(1-naphthyl)propionic acid
NBS: N-bromosuccinimide
Ph: phenyl(R)-(S)-PPFA: (R)-N,N-dimethyl-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethylamine
PPTS: pyridinium p-toluenesulfonate
PIFA: [bis(trifluoroacetoxy)iodo]benzene
Pin: pinacol
Pr: propyl
SPhos: 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl
TBAF: tetrabutylammonium fluoride

TBS: tert-butyldimethylsilyl
TFA: trifluoroacetic acid
TFAA: trifluoroacetic anhydride
Tf: trifluoromethanesulfonyl
THF: tetrahydrofuran
TMS: trimethylsilyl(o-tol)3P: tri(o-tolyl)phosphine

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2

Type 1
OH

O
O

O

O

R

OH

OH

O

O

O
O

OH

HO

OH

Riccardin B 6)
isolated from
Riccardia multifida

Marchantin A 5) : R = OH
Marchantin C 5) : R = H
isolated fromMarchantia polymorphaIsomarchantin C 7)
isolated fromMarchantina polymorphaType 2
OH
O

O

O

HO

OH

OR1

R

O

MeO

R 2O
HO

HO

Riccardin C (3) 6)
isolated from
Reboulia hemisphaerica

Riccardin A 6) : R1 = H, R 2 = Meisolated from Riccardia multifida
Riccardin F 8) : R1 = Me, R 2 = H
isolated from Blasia pusilla

OH
R
Plagiochin A 9) : R = OH
Plagiochin D 9) : R = H
isolated from
Plagiochila acanthophylla
subsp. japonica

Type 3
OH

OH

OH

HO

OH

OH

Cl

HO

HO
HO

Isoplagiochin C 9)
isolated from
Plagiochila fruticosa

HO

HO

Isoplagiochin D 9)
isolated from
Plagiochila fruticosa

Bazzanin A 10)
isolated from
Bazzania trilobata

Type 4
OH

HO
OH

HO

O

O

O

O
HO

HO
HO

HO

HO

HO

O
Asterelin A (1) 11)
isolated from
Asterella angusta(+)-Cavicularin (2) 12)
isolated from
Cavicularia densa

Pusilatin C 13)
isolated from Blasia pusillaFig. 1-1 Subtypes and representative compounds of macrocyclic bisbibenzyls.9)

2

OH

OH

 ÁĭĦ`M`dqLnƞ'&ĥĳ$Ďƃ%ýį$ĮĤęâ5ý2-&ÀĮĤęâĤŽ"2 14) ( hn?qTq A 'őŝĒâ-Ęĺ35',"

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2 15) 7MWomq A (1) 'ļŨ CandidaþÛ3

MIC = 128 µM &ĠÖ!êļŨęâ5ý 11) cKlTq C ' IC50 =albicans %Ë%3 2)

5.16 µM &ĠÖ! DNA gmilrO β ęâ&ƒÉ5ł"ù0*9Pm?nX8q C ' IC50 = 45.2−58.0 µM &ĠÖ%KCp>AKF[rO (COX) ƒÉęâź,039Phn?qTq C ' 10 µM &ĠÖ!?WcKq L "B &ƊŐęâ5©95%93%ƒÉ2"
hemisphaeria42 2)0%Ŧƞ Reboulia0¤Ɨ3m?nX8q C '10−100 µM &ĠÖ!ąoNcRr!2_YŚš X oNcRrα (LXRα) &ĥĳĸ7H\MYęâ5ý2"¢ū°Ɵ°ŰĮĿņè&üu0&Dnrc%/1ù0
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2 16)

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OH

OH

O

%3āĉőŝ

µň

OH
OH

O

OH

OH

HO

OH

OH

O

HO

MeO

O

O

O

HO

O

Marchantin A

Plagiochin A

Asterelin A (1)Isomarchantin C• Cytotoxic activity• Neurotrophic activity• Antifungal activity• Cathepsin L and B inhibition

HO
OH

OH
O

OH
O

O

O
OH

HO

HO

HO
HO HO

HO

HO

Isoriccardin C

Pusilatin C

Riccardin C (3)• Cyclooxygenase inhibition• DNA ploymerase β inhibition• Selective LXRα agonist activity

Fig. 1-2 Biological activities of macrocyclic bisbibenzyl compounds.
3 ÁĭĦ`M`dqLnƞ&ĥĳ$Ďƃ"Ť®ĝĮĤęâ'yız&ªå
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 Fig. 1-3 %R9c 1 %ƞ32`M`dqLnƞ&ªå5ł 17) xİ0
' Ni ŶÂ5į Wurtz ¦ß%/1Á±ĭ5Ďōm?nX8q B &ªå 18) 52*ĩ0' Horner−Wadsworth−Emmons ¦ß%/2hn?qTq A

Ɔå&ªå 19) Speicher 0' McMurry ¦ß!hn?qTq C &ªå 20) 5¼­

2R9c 2 &ªå%

3&ªå-dqLnƐ&Ǝĭ¦ß!Á±ĭ5Ďō-dqLnƐ!&Á±ĭĎō1

1Nogradi 0' Wurtz ¦ß{Ě"$%/2m?nX8q A &ªå 21) Speicher 0' Wittig ¦ß%/2m?nX8q C "McMurry ¦ß%/2clL>Tq E &ªå 22) ńÐ0' Stevens ¦ß%/2clL>Tq D &ªå 23)5¼­

2 (Fig. 1-4) *²sƍÿ0&Dnrc'ťơøŖð¦ß5<rWnƉ!&ĭ¦ß%ƈįm?nX8q C &ªå5¼­

2 24) R9c 3 &ªå%

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

1

Speicher 0' Wittig ¦ß%/19PclL>Tq C 25) 50%^J\q A 26) 'McMurry ¦ß5į2"!33ªå5ƆåType 12 (Fig. 1-5)

O• Wurtz reaction• H−W−E reaction• McMurry reaction• Wurtz reaction

OMe

O

Cl

O

OH

O
1) NiBr 2(PPh 3)2, Zn, Et 4NI, 83%

Cl

Riccardin B 18)
M. Iyoda et al.

2) BBr 3, CH2Cl2, 95%
O

OMe

O

OH

• H−W−E reaction
O

O

O

O

OH
OH

1) t-BuOK, DMF, 60%
OHC

P(OMe) 2OO2) H 2, Pd/C, MeOH, 89%
3) 6N HCl, 80%

Marchantin A 19)
M. Kodama et al.
O
OH

OBn
• McMurry reaction
O

OHC
O

OH

CHO

O
1) TiCl4, Zn, THF, 47%2) H 2, Pd/C, 96%3) BBr 3, CH2Cl2, 85%

OH

OH

Marchantin C 20)
A. Speicher et al.
O
OH

Fig. 1-3 Total syntheses of type 1 macrocyclic bisbibenzyl compounds.
4Type 2O

• SN Ar reaction• Wurtz reaction• Wittig reaction• McMurry reaction• Stevens reaction• Wurtz reaction
OBn

OH

O

O

Br
1) Na, Ph 2C=CPh2, 30%

Br2) BBr 3, CH2Cl2, 37%

MeO

Riccardin A 21)
M. Nogradi et al.

MeO
HO

BnO
• Wittig reaction

OH

OMe

O

O
1) NaOMe, CH2Cl2, 80%
CHO
PPh 3Br

MeO

Riccardin C (3) 22)
A. Speicher et al.

2) H 2, Pd/C, 92%3) BBr 3, CH2Cl2, 80%

HO
HO

MeO

• McMurry reaction
OMe

OH

O

O

OHC

CHO

1) TiCl3(DME) 2, Zn, DME, 23%

Plagiochin E 22)
A. Speicher et al.

2) H 2, Pd/C, 98%3) BBr 3, CH2Cl2, 68%
OMe

OMe

OH

OH

• Stevens reaction
OBn
O

O

Br

MeO

DMF
25%

O

1) Anthranilic acidisoamyl nitrite
ClCH2CH2Cl

Na 2S(0.01 M)
Br

OH

OBn

S
MeO

OBn

OBn

2) Na, t-BuOH
3) H 2, Pd/C, EtOH
1%, (over 3 steps)

MeO
OH
Plagiochin D 23)
Y. Fukuyama et al.

• SN Ar reactionO
p-Tol S
F
HO

OH
OMe

O
1) CsF, CaCO 3, 3AMS
DMF, 140 °C, 92%2) n-BuLi, then MeOH, 95%
3) BBr 3, CH2Cl2, 93%,

MeO

Riccardin C (3) 24)
K. Suzuki et al.

HO
HO

MeO

Fig. 1-4 Total syntheses of type 2 macrocyclic bisbibenzyl compounds.
5

Type 3• Wittig reaction• McMurry reaction• Wittig reaction
OMe

OMe

OH

1) NaOMe, CH2Cl2, 74%

PPh 3Br
MeO

OH

2) BBr 3, CH2Cl2, 85%

CHO

Isoplagiochin C 25)
A. Speicher et al.
HO

MeO

HO

• McMurry reaction
OMe

OH

OMe
Cl

OH
Cl

1) TiCl3(DME) 2, Zn-Cu, DME

CHO

Bazzanin A 26)
A. Speicher et al.

2) BBr 3, CH2Cl2, 85%
MeO

HO

CHO

HO

MeO

Fig. 1-5 Total syntheses of type 3 macrocyclic bisbibenzyl compounds.
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6

O

• Stille−Kelly reaction• Suzuki−Miyaura reaction

Type 2Type 3• Stille reaction
Type 2
R1

O

R1

O

R1

Pd(PPh 3)4(Me 3Sn)2

MeO
R1

Br

Toluene120 °C44%BrR1

R1 = MOM

OH
R1 1) Pd(PPh 3)4
Toluene120 °C, 31%

MeO
R13) HBr, MeOH
71%

R3

R2

OH

O

MeO

R1

OH

HO

R1 = MOM, R 2 = Br, R 3 = SnMe 3
or
R1 = MOM, R 2 = SnMe 3, R 3 = Br

Plagiochin A 23)• Stille−Kelly reaction
Type 2OMOMOOPd(PPh 3)4(Me 3Sn)2

MeO
Br

OH

OMOM

O

Toluene120 °C, 17%

Br

HBr
MeOH
87%

MeO

OMOM

MeO
OH

OMOM

Plagiochin D 27)• Suzuki−Miyaura reaction
Type 2OOOO
Pd 2(dba) 3, SPhos
2M Na 2CO 3

O
B

OH

OMe

OMe

DMF, 100 °C
48%

TfO
OMe
MeO

BBr 3
CH2Cl2
97%

MeO

HO
HO

MeO

Riccardin C (3) 28)
Type 3

OMe

OMe

O
O B
OMe

OMe

OMe

OH

OMe

Pd(PPh 3)4, K 3PO 4

BBr 3

DMF
80 °C, 41%

CH2Cl2
86%
MeO
MeO

OTf

OH

HO
HO
Isoplagiochin D 29)

Fig. 1-6 Our synthetic studies on bisbibenzyl compounds using Pd-catalyzed reactions.
7

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Type 4
OH

HO

O

O
HO

HO

HO
O
(+)-Cavicularin (2)Asterelin A (1)Fig. 1-7 Synthetic targets.
 sĺ&ªåRrFUY!27MWomq A (1) '2007 Ô% Lou 0&Dnrc%/1Ŧƞ Asterella angusta0¤ƗĎƃĕÆ3`M`dqLnƞ!1Á±ªĤ!2 (Fig. 1-8) 11)

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2ī·4þÛµ!ŢÕÌ3

2êļŨū'{% 4 ClM 7 Ņƞ&+!1{ų$êļŨū%ūřâ&³ƝĮ2"ļŨäĄĵĖĶ%ĝ$Úƛ5x2,õ$įĐĎ5ý2êļŨū&Əķ


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2


OH
O
A

HO

B

C

D
Dibenzofuran

O

Asterelin A (1)Fig. 1-8 Properties of asterelin A (1).
8

2 30)
3*!%ģ -s&ªåRrFUY!2 (+)-?`Clmq (2) '1996 ÔěÒñí&Dn
rc%/1Ŧƞ Cavicularia densa
qĎƃ5ý2ƥÖ%đ+&0Ŵ3ĭĦĎƃ

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Gqa=irKkq5Ùå 2&Ļ$Gqa=irKkq'Ɓwô5Į[α]D21 +168 &ē÷Ö5ëÄęâªĤ'Ŧz%

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2 (Fig. 1-9)

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Dihydrophenanthrene

1

A

HO
O C

1

212°

HO

1 O Ar

O

165 °

A
7

D

7

B

OH

HO

163 °

HO

CH
7 2
A ringHO(+)-Cavicularin (2)[α]D 21 +168 (c = 0.25, MeOH)

Fig. 1-9 Properties of (+)-cavicularin (2).
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' 3’" 10’Ɛ!&Ƌ

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OH
O
C-10 and O-13'
OH
O
A

C

HO
Oxidative
couplingO

3'

Asterelin A (1)

10'

HO

D

B
10

HO
O

C-3' and C-10'

HO
O

OH
13'

Oxidative
coupling

HO

Riccardin C (3)
HO

OH

HO

(+)-Cavicularin (2)Fig. 1-10 Plausible biosynthesis of asterelin A (1) and cavicularin (2) from riccardin C (3).
9 ŪŘ'&ĮªåŒƀ5àƜ%`a;\nœªÙå¦ß"ÃƋD¦ß%/27MWomq A (1)?Ucmq/) (+)-?`Clmq (2) &ªåĿņ5ů"%$4Pd ŶÂ¦ß5ęį2æ&çĲ5ßįÁ±ĭ5ĎōÜ13’&ĔƋ»

0LdqQalqƤć510’&ĢŐ

0'L_Zpa;[qYoqƤć

533Ďō2Įªå%ªåė5Čŷ2"% ØĿņÇ!Ŕ/1sƄ&ÁĭĦ`M`dqLnƞ&ªåĿņ'1ªĤ&ªåĿņ/) 2 &ªå%Å|2"%$1ĂĿņ5ÁĭĦ`M`dqLnªĤªå&ƕÁå"Ŗ3*!ůÁĭĦ`M`dqLnƞ&ªå

çĲ.éė5üÁƔ%ęį2ªåĿņ%Ľé vĂŻó&Ŋsŉ!'7MWomq A (1) &ªå%

*Ŋ~ŉ!'(±)-?`Clmq (2) &ªå% 0%Ŋtŉ!' (+)-?`Clmq (2) &w
ôªå%ŹƂ2

10īĪ ;LUrpt A '¨ÞīwĮÐŚ
 ;LUrpt A (1) (»đč`L`ftKqƁ'|"¯wKftQbotóŠ:ì6¨ċ"6"%ŊĽÚĠŇĘ&È6ç%úęŊ#%5

6Jv

X¨ċ"6#41

4ÍÏŬ'ĦÁļ

4üĝ:Ż0!6'¨Þ(7."&µ«(%'¨Þû'ŴĚ%

ù047!6îģĨ"('Čė%óŠ'¨ÞûĤĩ:ĝâ;LUrpt A 'Ē¨ÞĵŞ&´¨Þ

%#& (Fig. 2-1)

ģĨ:

OH

OH

O

O
C-10 and OH-13'

HO

Oxidative coupling

D

B
10

HO

OH

O

13'

Asterelin A (1)Riccardin C (3)Fig. 2-1 Biosynthesis of asterelin A (1).
 ;LUrpt A (1)ì6KftQbotóŠ(º'¼Ċċ'ŧóŠ#!

ġ47!6&1Ŷ94KftQbot'óįû(}&xħƁ'¤Ø&Ÿ47!
6wĝ(]sGt:ì6`b?Zq@vUq¨ċ¤Ø"

31a-i)

6

32a-b)

4'ćĳ−ćĳĶ¨ÓÞĝ(]sGtb?Zq#b?\vq#'ćĳ−ŪĳĶ¨ÓÞ¤Ø"'ħƁ'KftQbot'óįû(]sGt2''ĿŽ´:

ĺťáĜ&É6×ŏ5¨Þ'İ#Ĉ&xĝ'óįû#%6b?\vq
sGt'É

!°ƀ

6wè

4'ĞäĜ%¿ŪCTdptF¤Ø(]×ŏ%İ%¨Þû#6

¼Ċċ¨Þ&ē7(žÌ&Ê%.5wńĜ"%ŪCTdptF:Øē¨Þ#!
Pan 4&36ĺťáĜ¿ŪCTdptF:Ų# (±)-;YLRSt B '
¨Þã476 (Fig. 2-2) 33) 

6ýÚ'¤Ø"(ƆŅ"ĥbpv'øŪ´&3

KftQbot'ÓÞ&×ſ#7!6îģĨ"t¨Þ"(KftQbotŧ¹&bpv'øŪ´¤Ø%;LUrpÀ³6#'ĭß"'ŪÝÙ760Ğä'¨Þû:Ťē6#("%"îģĨ"(KftQbotđÓÞ'/Ţŋ60¤ØĈ¹'øŪ´:lSq@vUq"ś´ŝ&È6b?\vq'ĞäĜŪCTdptF:òŕ6#& (Fig. 2-3)
îĪ'Æ&Ŷ!( Nat. Prod. Comm., 8, 915−918 (2013) &ĚŌĂ/
11

X

Cl

Ar− Ar coupling

O

O

OMe

O

Pd(OAc) 2
PCy 3-HBF4
K 2CO 3OMe

O

DMA, 130 °C
81%

X = Halogen, CO2H, H

K. Fagnou et al.

O

O

X

OH

S

S

Pd or Cu-catalyzed
O-arylation
O

CuTC

N
Et

HO
Cl

N
Et

O

DMA, 130 °C
65%

X = Halogen

BINDY
M. Hagiwara et al.

OH
OH
Oxidative
coupling

HO
HO

OH

HO
O

HO

HO

HO

OH

1) Ag2O, DMF
OH
50 °C, 75%

OH
O

O

2) H 2, Pd/C
EtOH, 98%

O
OH O

OH O

(±)-Anastatins B
G. Pan et al.

Fig. 2-2 Examples of construction of dibenzofuran.


OMe

OMe

O

O
Oxidative coupling

MeO

MeO
HO

O

Fig. 2-3 Oxidative coupling for dibenzofuran of asterelin A (1).

12īĮ ¨ÞŔĔ î¨Þ"(;LUrpt A (1) 'Ē¨ÞĵŞ&´

KftQbot'óį(¨Þ'ëĴ÷ź"ŋ#&"(ŪCTdptF&ĺťáÚ:10¨ċ 4 '3& 3 6b?\vqÚøŪ´' 2 :lSq@vUq#6×ŏ6¨ċ 4 '»®đóį(ÒģĨÄ"ĤĩpCqV<t C (3) '¨Þû 28) &ÕPd œ¾¿ůí−Åþ¤Ø&35óį6#&đƃ
5 ( A−C đ&ğÒ6`b?Zq@vUq 8 & B đnZTW 7 # C đnZTW 6 : 2
Ñ' Horner−Wadsworth−Emmons (HWE) ¤Ø&35šĶ6#"¨Þ6#&4&`b?Zq@vUq 8 (¨ċ 9 # 10 ' Ullman ¤Ø&35řō6ŔĔ"
6 (Fig. 2-4)

OMe

OH
O

O

C-10 and OH-13'
Oxidative
coupling

OMe
Intramoleculer
Suzuki−Miyaura
reaction

3'

O
O

O

A

C

B

10'

MeO

HO

10

O

B

TfO
D
OMe
RO

D
HO

13'

4

Asterelin A (1)5H−W −E
reaction

OMe
Br
A

HO
C

A

OHC

OMe

Br

C

B

CO2Me

OMe

O

Ullman reaction
OHC
CO2Me

10

9

8

O
P(OMe) 2

D
OMOM
OBn

7

Fig. 2-4 Retrosynthetic analysis of asterelin A (1).

13

CHO

6

īĮ¿ůíÅþ¤Ø&36»®đóį §nZTW'řō

4îģĨ:Ŵ½ËŜ' 3,4-K_XsDJftM;qV_X(11) :;NWtĆ¾|ćŪCp>k#ŀftKq"ď¨ċ 12 : 63%'¥Ď"Ö12 'øŪ´: N,N-K=Pdsaq@Sq;jtÀ³z MOM ´"śDđnZTW 6 :řō (Fig. 2-5)

CHO

CHO

CHO

BnBr, K 2CO 3

MOMCl, DIPEA
D

OH
OH

Acetone, reflux
63%

OH
OBn

11

OMOM
OBn

CH2Cl2, 0 °C
84%

12

6

Fig. 2-5 Preparation of unit 6.
 B đ n Z T W 7 (  2- c s m -5- l W D J f t K q c s j X (13)4Michaelis−Arbuzov ¤Ø 34) :ŋ%#&35 1 ÷ź 98%'¥Ď"¨Þ (Fig. 2-6)
Br
Br

P(OMe) 3

Br

reflux
98%

B

OMe

O
P(OMe) 2

OMe
7

13

Fig. 2-6 Preparation of unit 7.
 AC đnZTW&ğÒ6`b?Zq@vUq 8 (3-_XsDJ-4-lWDJÂ
ÛƂŪlSq (9) # p-csmftM;qV_X (10) :apKtĆ¾|Ūű£)
ćŪCp>kÀ³z Ullman ¤Ø:ŋ#" 76%'¥Ď"řō (Fig. 2-7)

OMe

OMe
Br

HO

CuO, K 2CO 3

+
OHC
CO2Me
10

O

Pyridine, reflux
76%

A

C

OHC
CO2Me
8

9

Fig. 2-7 Preparation of unit 8.

14 õ&¨Þ§nZTW: 2 Ñ' HWE ¤Ø"šĶ+!'ņƂđšĶ¨ċ 18 *É (Fig. 2-8)THF Ć¾| 0 °C "nZTW 7 :øĳYWp>k"ďÔnZTW 8 #' HWE ¤Ø&35 98%'¥Ď" 14 :Öķ! 14 '@LUqŧ:øĳ;qjZ>kpS>k"Ŧ;qHvq 15 : 98%'¥Ď"řō4& 15 ';qHvq:ŀSBZq&35ŀĳÔıō6#ĉptŪWplSq#¤ØhLh[vW 17 *ŘÉÖ47hLh[vW
 17 : HWE ¤Ø&35nZTW 6 #šĶ94%'¥Ď"¨ċ 18 *É%$4' HWE ¤Ø1ÃĐ% E ťáÚ"¤Ø(Ţ/Z (Ö47!%
OMe
OMe

Br

O
A

C

+

OHC
CO2Me

OMe

O
O
P(OMe) 2

B
OMe

NaH

O
LiAlH 4

Br

OMe
14

15
SOBr 2, Benzene
0 °C - r.t.

CHO

OMe

D
OMOM
OBn

O

NaH
OMe

OMe
O

Br

18

Br

reflux98%(over 2 steps)

O
OMe

OBn

Br

P(OMe) 3(MeO) 2 P

THF
0 °C, 94%

MOMO

OMe

O

6

Br

HO
OMe

7

8

Br

CO2Me THF, 0 °C
98%

THF, 0 °C
98%

OMe

17

16

Fig. 2-8 Horner−Wadsworth−Emmons reactions between 7 and 8 / 6 and 17.
 !Ö47¨ċ 18 &ÈLSqft'Ŧ¤Ø:òŕ (Table 2-1).
Zdanovich 4'èû 35) &ÕWpbqBsũŪÀ³zJotŦ:ŋ#B
rb<t'Ŧ(Ţŋ1'' MOM ´#ŀĳ'ĿŽ
Þċ#!{

 (Entry 1)õ&ÒģĨÄ'

Ŀcsm 20 :}Ē

&doKBSt'¨Þ&ēeDIt/ftOtā¨Ć¾|ŪěŮ:œ¾#!ē6ï

:Ŗ/#8 23)ŒĄ7¨ċ 21 #Ŀcsm 22

Ö47 (Entry 2)

¤ØĞÔ

4ŀĳ'ĿŽ

Ć¾:Esshqk/lR\vqā¨Ć¾&¸ê¤Ø:Ŗ/Ő47%

 (Entry 3)õ&·´Úïē6_XoKtŦċ 19 :řō"36a-b)Ķð&»%¸(z p−Wq@tLqbAZq_XoKX::ŋ#8Ŀŀĳ:ŷ#"ƅ¥Ď"ĝĜ

 (Entry 4)4&Ć¾#!@WDJ@R\vq:ē#8¤Øéŵ'ĢĹ&1Þ¥Ď: 97%."æ±"15 (Entry 5)

OMe

OMe

O
Br

OMe

OMe

O

OMe

O

Br

O

Br

OMe

MOMO

OMe

O

OMe

MOMO

OBn

18

OMe

HO

OBn

OMe

MOMO

OH

19

MOMO

OH

OH

21

20

22

Table 2-1 Selective reduction of the double bonds in the stilbene.
products (%)
entry

conditions

18

19

20

21

22

1 Et3SiH, TFA, 60 °C, 25 min

−

−

74

−

−

2 H2, PtO2, Benzene/Hexane = 1:1, r.t., 2 h

22

−

−

35

12

3 H2, PtO2, CHCl3/MeOH = 9:1, r.t., 2 h

23

−

−

53

7

4 TsNHNH2, NaOAc, THF/H2O = 1:1, 70 °C, 6 h

−

94

−

−

−

5 TsNHNH2, NaHCO3, EtOC2H4OH, 135 °C, 3 h

−

97

−

−

−

 õ&Ö47 19

4»®đđƃ 24 *ŘÉ (Fig. 2-9)19 :Esshqk⁄lR\vq = 9 : 1 'ā¨Ć¾|äœŦ&35ftKq´:Ź¡ÔWpbqBsl
RtLqhtŪĉøċ£) N,N-KlSq-4-;j\apKt"ďWpbrvW 23#ķ!Åþ¤Ø&35istŪ@LUq:Éđƃ 24 :řō

OMe

OMe

O

O
Br

H 2, Pd(OH) 2

OMe

MeOH/CHCl 3 = 1:9
93%
MOMO

Br

OMe

MOMO
OH

OBn
19

21
Tf2O, DMAP
CH2Cl2, 96%
OMe

OMe

O

O
O

B

O

B 2pin 2, Pd(PPh 3)4, K 3PO 4
Dioxane, 100 °C
81%

OMe

MOMO

Br

OMe

MOMO

OTf

24

23

Fig. 2-9 Preparation of boronate 24.
16

OTf !ÖistŪ@LUq 24 &È!¿ůí−Åþ¤Ø:òŕ.
©ô'ĵŞ"řōmVq¨ċ'WplSq@vUq 27 &Èůí−Åþ¤Ø:ŋ (Table 2-2)DMF Ć¾|œ¾#! Pd(PPh3)4·´#!ptŪCp>k:ē!¤Ø:ŋ# 9%#¥Ď"(6ĝĜ'đ 28 :Ö6#"(Entry 1)õ&ħ'œ¾#Ũ¿:òŕĶðœ¾& Pd2(dba)3Ũ¿& SPhos:ē#

¥Ď'ªyŗ0474&·´'ħƁ:òŕ#82 M 'ćŪYWp>køĆÿ:ē¶¨25%'ŭ 29: 48%'¥Ď"Ö6#
ð&!1òŕ& Entry 3 'ï"ĒÞ1''ĝĜċ 28

 (Entries 2, 3)ê%6¥Ď'æ±:ĝâ!Ć¾

¥Ď'æ±&(Ł4% (Entries 4-6)y'ġŐ:1#:îĖ'´ŝ#%6¨ċ 24 *Ťē#8¥Ď'z /47ĒÞċ#!dsWĿh>ĳ7 26

65%'¥Ď"ĒÞ (Entry 7)'dsWĿh>ĳ(Ĳ&À³6ø¿dsWtą#%5¤Ø#Ļ

470·´:ćŪYWp>køĆÿ

Ţŋ!64ĉøćŪYWp>k&¸ê.Ć¾' DMF (¤ØĞ&ŉĕ1':ē#8Üş5dsWt:à6#72%'¥Ď"»®đ¨ċ 25 :Ö6#&Þ (Entry 8)

"

OMe
O
OMe

OMe
O
O

B

Pd cat.
20 mol% Ligand
3 eq Base

O

OMe

RO

OMe

O

O

MeO
OMe

Solvent
MeO(0.005 M)
12 h, 100 °C

OMe

RO

MOMO

OTf

24: R = MOM
27: R = Me

PCy 2
OMe

MeO

MeO

25: R = MOM
28: R = Me

OTf

26

OMe
O
OMe

29

SPhos

Table 2-2 Intramoleculer Suzuki−Miyaura coupling of 24 and 27.
entry

R

Pd

ligandsolvent

baseresult1

Me

Pd(PPh3)4a

−

DMF

K3PO4

28 (9%)2Me

Pd2(dba)3b

SPhos

DMF

K3PO4

28 (16%)Me

Pd2(dba)3

b

SPhos

DMF

2M Na2CO3

28 (48%), 29 (25%)

Pd2(dba)3

b

SPhos

Toluene

2M Na2CO3

28 (2%), 29 (28%)

b

SPhos

THF

2M Na2CO3

28 (34%), 29 (24%)

3
4

a

Me

5

Me

Pd2(dba)3

6Me

Pd2(dba)3 b

SPhos

DMSO

2M Na2CO3

28 (3%)

b

SPhos

DMF

2M Na2CO3

25 (31%), 26 (65%)

SPhos

DMFd

anhydrous
Na2CO325 (72%)7MOM

Pd2(dba)3

8c

MOM

Pd2(dba)3 b

10 mol%. b 5 mol%. c 0.001 M. dFreshly distilled DMF was used.
17 õ& 25 :lR\vq⁄ũŪ@Sqā¨Ć¾|ŪÚïz MOM ´:Ź¡Ö4

7b?\vq 4 &È!Ų¤Ø"6¿ŪCTdptF&36KftQb
ot'óį¤Ø:òŕ6#&

OMe

OMe

O

O
Dowex ® 50WX2−100
MeOH/EtOAc = 2:1
70 °C
83%

MeO
MOMO

MeO
HO
4

25

Fig. 2-10 Deprotection of MOM group.

ī²Į ¿ŪCTdptF&36KftQbot'óį#;LUrpt A '¨Þ 1980 Î& Harrod 4'Fqvd(BDJ·^YK>k(V) :Ū#6b?\vq'ŪCTdptF:µ«!

5'ĒÞċ'w#!¥Ď%

tQbot¨ċ:Ö!6 37)

OH

OH

OH
t-Bu

Hexane
25 °C

t-Bu

OH

t-Bu

t-Bu

2 eq. VOCl3

t-Bu

t-Bu

t-Bu

t-Bu

15%

OH

OH

O

O
Oxidant

HO

HO
HO

O

Asterelin A (1)Riccardin C (3)Fig. 2-11 Oxidative coupling using VOCl3.
18

Cl

t-Bu

t-Bu

t-Bu

10%

67%

O

4Kf

 "ňļ( Harrod 4'Ķð:¢Ļ&Ū:ē6¿ŪCTdptF:òŕ (Table 2-3).q=LŪÀ³zŪ#! 4 'øŪNp>k:ē!¤Ø:ŋ#Ŏż%ā¨ċĒÞ6'/"ĝĜċ:Ö6#("%(Entry 1)õ&KEsslRtĆ¾|Ū#! PIFA :ē!Äă"¤Ø:ŋ
#85%#¥Ď"(6 ;LUrptƄñ:ì6 30

Ö47Ū

:x'·Ű&¸ê¤Ø:ŋ¶¨"1,-©Ĭ'¥Ď"ĝĜċ:{(Entries 2, 3)wèŪ#!BDJ·^YK>k (V) :ē! 15 éŵ¤Ø¶¨ĝĜċ 30 (Ö47%¨ċ 31 ;LUrptƄñ' 10’

Ess720Ƈ'¥Ď"Ö47 (Entry 4)'¤Ø"(KftQbotƄñ'ÓÞÔ10’'Ess£)¿ŵ'ū¨Ţŋ!6#Ą70©

¤Ø: 20 "ö#830 : 58%'¥Ď"Ö6#&Þ (Entry 5)
Ń¬Ā#&7'ï

1 10’ćĳy"'ŪCTdptF¤Ø(ŢŋÈØ6K_Xsb?YtWrt 32 (Ö47!%
OMe

OMe

O

OMe

O

10'

MeO

MeO
HO

Cl

MeO
O

4

MeO
O

O

32

31

30

OH

MeO

O

Table 2-3 Oxidative coupling of 4.
entry

oxidant

conditions

time

30 (%)

31 (%) 32 (%)

1Ce(OH)4 TFA, TFAA, BF3uEt2O, CH2Cl2, −78 °C 18 h complex mixture

−

2

PIFA

CH2Cl2, r.t.

16 h

5

−

−

3

FeCl3

CH2Cl2, r.t.

22 h

7

−

−

4

VOCl3

CH2Cl2, 0 °C

15 h

−

20

−

5

VOCl3

CH2Cl2, 0 °C

20 min58

27−

 Fig. 2-12 &(BDJ·^YK>k (V) &36ŪCTdptF'¤ØlCZMk:ĻÇBDJ·^YK>k (V)D đy'øŪ´#Ķ¨'oKCq

ĚĒšųĜ& B đ' 10 #đ:ÓÞÔëÔ& 10 'dsWt"KftQbotÓÞ76#åĄ76

19

ĿŽ6#

OMe
O

MeO

B

OMe

O
Cl V Cl
Cl

O

OMe
O

D

MeO
10

10 HO

4

MeO

O
V

Cl

OMe
O

Cl

O
Cl

Cl

OH
V

O
V

Cl
Cl

O
V

Cl
OMe

Cl

O

MeO

Cl
10

O

MeO
V O

O
Cl

30

H

O

Fig. 2-12 Plausible mechanism of oxidative coupling with VOCl3.
 Fig. 2-13 &(ĒÞċ"6Ess 31 '¦ľ%ĒÞlCZMk:ĥKftQbotƄñ'ÓÞÔBDJ·^YK>k (V)

4Ĳ"Ē·ĳoKCq

đ' 10’&ĿdsWt6#" 31ĒÞ#Ļ

Cl

O
V

O

Cl

V

Cl
OMe

OMe

OMe

O

O

O

Cl

Cl

Cl

10'

H

Cl

−HCl
MeO

MeO

MeO



O

O
30

O
31

Fig. 2-13 Plausible mechanism of chlorination giving rise to by-product 31.

20

D ëÔ&ŪCTdptF&35Ö47 30 :xŀh>ĳ"ď!lSq@v
Uq´'Ŀś:ŋ 17 ÷ź 6.4%'ĸ¥Ď";LUrpt A (1) '¨Þ ţÞ" (Fig. 2-14)
OMe

OH

O

O
BBr 3
CH2Cl2, 0 °C
76%

MeO
O

HO
O
Asterelin A (1)Total 17 steps
6.4% over all yield

30

Fig. 2-14 Completion of the synthesis of asterelin A (1).
 Fig. 2-15 &¨Þ­' NMR LgEWq:. Table 2-4 &¼Ċċ#¨Þ­'LgE
WqVvR (1H NMR, 13C NMR) 'wő:ĥ 11) ¨Þ­'LgEWqVvR(¼Ċ
ċ'LgEWqVvR#wł7&35;LUrpt A (1) '¨Þ:Ã~

1H NMR of synthetic 1 (500 MHz in (CD ) CO)
3 2

13 C NMR of synthetic 1 (125 MHz in (CD ) CO)
3 2Fig. 2-15 1H and 13C NMR spectra of synthetic 1.

21

2
3

OH
1

4

6

7

3'

5

4'

11' 10'9'
14 12'

12 13

13' 14'

HO 11

O

6'
5'

8

9

10

1'

O 2'

7'
8'

Asterelin A (1)Table 2-4 Comparison of 1H and 13C NMR between natural and synthetic asterelin A.a
Position

1
2
3
4
5
6
7
8
9
10
11
12
13
14
1'
2'
3'
4'
5'
6'
7'
8'
9'
10'
11'
12'
13'
14'
     aNatural11 
δH (600 MHz)δC (150 MHz)
157.36
6.61, dd (2.6, 8.3)
121.56
7.47, dd (2.2, 8.3) 
131.98
136.31
5.98, dd (2.2, 8.2)
130.78
6.29, dd (2.6, 8.2)
119.99
2.73, m39.32
3.23, m
3.34, m35.13
3.47, m136.55
6.83, d (2.1)
113.07
157.98
6.87, d (2.1)
98.81
158.36
117.35
147.79
146.38
5.33, d (1.7)
122.22
133.30
6.84, dd (1.7, 8.4)
125.43
6.84, d (8.4)
116.67
2.77, m38.09
2.98, m3.13, m38.46
2.58, m
139.38
6.28, dd (1.4, 7.9)
124.78
7.14, d (7.9)
121.42
122.93
157.117.26, d (1.4)
110.73Synthetic δC (125 MHz)
158.0
6.61, dd (3.0, 8.5)
122.2
7.47, dd (2.0, 8.5) 
132.6
137,0
5.98, dd (2.2, 8.0)
131.4
6.28−6.30, m
120.6
2.71, dd (3.5, 13.0)
40.0
3.22, ddd (3.5, 3.5 ,13.0)
3.33, ddd (3.5, 3.5, 13.0)
35.8
3.45, ddd (3.0, 13.0, 13.0)
139.2
6.84, d (2.0)
113.7
158.6
6.87, d (2.0)
97.5
159.0
117.3
148.4
147.0
5.33, brs
122.9
133.9
6.83, brd (8.6)
126.1
6.83, brd (8.6)
118.0
2.76, dd (3.5, 12.0)
38.7
2.97, ddd (3.5, 3.5, 13.5)
3.12, ddd (3.5, 5.5, 13.0)
39.1
2.57, ddd (3.5, 12.5, 12.5)
140.0
6.28−6.30, m
125.4
7.14, d (8.0)
122.1
123,6
157.8
7.25, brs
111.4
δH (500 MHz)In acetone-d6.

22įvĮ (±)-@[Clmr$¥áįuı ÒŒ
 ¹ĘĔ[I[_rHnų$|,­uŗyí5ô¿ĆÞ"GCp\7r¥ē1 (+)-@[Clmr (2) %{Ĝ|$¥á¿ľ$ąĢ5Ů+Ġ6#¥áĦĬ"421
 2005 Ñ Harrowven /%McMurry ¡Ý#.1¹¬ĘØá

lH@nĘ¡Ý#.1

$@[Clmr (2) $¥á5´©

H[Sp\<TrRorüĲ5Ũ

(Fig. 3-1) 38)$lH@nĘ¡Ý%Ģğē#Éęáē1m@nQ9r
C (3)1 : 2 $¥ęá1,$$@[Clmrŷù$üĲ#á1

HOO• McMurry reaction• Radical transannulation
OH

HO

MeO
O

A

OMe

MeO

C
O

OH

B
O

+

K 2CO 318−crown−6O

DO

PPh 3BrO

CH2Cl2
66%(E/Z = 2:1)

OMe

O

O

C

A
MeO

O

B
D

C
O
MeO

O

HO
O

10' I

CHO

D

CHO

MeO

1) TiCl4, Mg, THF
35% (Z selective)
2) TsNHNH2
NaOAc, 91%
OH

HO
O

OMe

O

O

1) HSi(SiMe 3)3, AIBN
Toluene, 90 °C

C+2) BBr 3, CH2Cl2
85% (over 2 steps)

HO
HO

OH

(±)-Cavicularin (2)

1: 2

I
D

MeO

HO

MeO

Riccardin C (3)D. C. Harrowven et al.

Fig. 3-1 The first total synthesis of (±)-cavicularin (2) by Harrowven’s group38).
öĮ$Æ#ū% Tetrahedron, 69, 6959−6968 (2013) #Ğňĉ)
23

 Harrowven /$lKe/ 8 ÑÚťõ/%BlnInaBGS5yíŉ³¥áÐ)#Ě1 (−)-@[Clmr$yí¥á5´© (Fig. 3-2)39)Ù/%½Ņŵðļë¡Ý#.1[\<Un=tPnĸ¥Øá¡Ý¹¬Ę5üĲÚlKe$InaBGS5BlnInaBGS'ļëŗyí$Ü5

"BlnĚ D Ę$Ï¤ŲÉĩ5

"ĸøŸInaBGS5yíŉ³#á1óÚ# Harrowven

=TrN?Ŝĕ5ĺæŗyí5üĲ1

/$lH@nĘ¡Ý5ÝĚHZSp\<TrRor5üĲ1 ºđē1 (+)-

$¥á#%ł"HO
O

• SN Ar reaction• Radical transannulation
OHHO

p-Tol S

p-Tol S O

O
F
A

O

OMe

HO

MeO

t-BuLi, THF−78 °CCsF, CaCO 3
MS3Å

R
DMF, 150 °C
92%

R

O

A

OMe

R
MeO

D

O
p-Tol SOMe

R = OMOM

then A, −78 °C
73%, 77%ee

R

R
MeO

D
R

R = OMOM

R = OMOM

OOS1) SnBr2, phloroglucinol
Toluene, rt., 82%2) n-BuLi, then MeOH, quant

pTol

A

(−)-Cavicularin (2)K. Suzuki et al.

1) HSi(SiMe 3)3, AIBNNa 2HPO 4, Benzene
82%

O

OMe

O

I
2) BBr 3, CH2Cl2
85%, >95%ee3) recryst. >99%ee

D

MeO
MOMO

(>95%ee)

HO
MeO

D
MOMO
(>95%ee)Fig. 3-2 Total synthesis of (−)-cavicularin (2) by Suzuki group39).

24

OMe

 /#2014 Ñ Beaudry /%ôþ½ō¼5Ě1yí Diels−Alder ¡Ý5Ũ¡Ýºđ²1 (+)-@[Clmr$¥á5+ŝá (Fig. 3-3) 40)$¥á%(H]ph_rLr#É1ŚĹťõÅć¡Ý#.0ŸÓ#ÂĿ³2
B−C−D ĘiUOR5qrcOR¥á$į~{ Grubbs ō¼5Ě?o\éōŠ#.0HZSp\<TrRor$üĲ5ŇĹ α,β-9rgMKGI

yŴªInar'ŐËÚGrFT8n@p:SŐË
α-pyrone Diels−Alder ¡Ý5Ň"ĸø78%ee,¹¬Ę5ôþ½ō¼

Ě1=TrN?şåÞ%|ĪÓ"/ŗyí5uç#üĲºđ²@[Clmr$yí¥á#á1

HOO• Diels−Alder reaction• Olefin metathesis
OH

HO

PhO 2S

B(pin)

Br

MeO

MeO

3

B

then

i-PrO
B(pin)

MeO

MeO

C

C

TBSO

RO

D

1) Grubbs II catalyst
CH2Cl2, 50 °C, 95%

D

Br

63%
(one flask)

OMe

B

RO

TBSO

2) H 2 (600 psi), Pd/C
EtOAc, 84%

OMe

MeO

OMe
MeO

R = i-Pr

R = i-Pr

CF 3
S
HN
N

N
H

CF 3
N

MeO

Cat. AO

1) NH 4CO2H
Pd/C, H 2
quant.

MeO
TfO

(+)-2
2) BBr 3, CH2Cl2
80%

MeO
MeO

M. Beaudry et al.

O

O
Tf2O
CH2Cl2
0 °C
45%
78%ee
(2 steps)

O

OMe

O
O
OH

PhO 2S
Cat. A
3AMS

O

45 °C
MeO
MeO

OMe
MeO

Fig. 3-3 Total synthesis of (+)-cavicularin (2) by Beaudry group40).

25

OHOMe

 $.

#{Ĝ|@[Clmr$¥áĦĬ"421|×ĦĬÄ$Í%ę¥áķŖ#³@[Clmr$¥áĦĬ5ũ» 41)Í% 2 $ę¥áŶ¥ē1m@nQ9r C (3) $¥áĄ5ħĭÚ3 $ţ@O^mrD#.1@[ClmrŷùüĲĄ$ũĞ#Ĥäű½œÈ"ŅŵĘ¦·$ţ@O^mrD¡
Ý#.0[\<Unĸ¥5Øá1µ¥ŕ½k;Ĵ¥ē-ţXTH;fİ
$ţ5Ě1¡Ý

ĥ/21ţ@O^mrD$óŞ"÷5èĵ

1+hQn³Ŕ 33 5őŊHZSp\<TrRor$üĲĄ5ûŏ (Table
3-1)ţ PIFA?BG\OXTH;f (V)4 $ĂţKm;f5Ě¡Ý5ûŏĸøPIFA 5Ě1 Entry 4 $÷#.0Ģğ$ 34
orŷù5, 35 522 33%28%$¢ĕÛ1

OMe
O



OMe
O

MeO

MeO

\<TrR

OMe
O

MeO

33

34

35

Table 3-1 Previous studies on oxidative coupling of the model compound 33 in our laboratory.
yield (%)
entry oxidant

conditions

time

33

34

35

1

PIFA

CH2Cl2, 0 °C

24 h

93

−

−

2

PIFA

BF3sEt2O, CH2Cl2, 0 °C

5h

35

22

23

3

PIFA

BF3sEt2O, MeCN, −40 °C

12 h

35

−

trace

4

PIFA

BF3sEt2O, CF3CH2OH, −40 °C

30 min

39

33

28

5

VOF3

TFA, CH2Cl2, 0 °C

4h

35

8

35

6

VOF3

TFA, TFAA, EtOAc, CH2Cl2, 0 °C to r.t

1h

27

−

10

7

Ce(OH)4

TFA, TFAA, BF3sEt2O

1.5 h

−

 hQn³Ŕ$ĸø5,#m@nQ9r C (3)complex mixture&RmgNnm@nQ9r C (36)5³Ŕţ@O^mrD5ûŏ (Table 3-2) 41)

ē5z1$)@[Clmrŷù5ô1 37 - 2 5Û1$ĸø/ņľ%ţ@O^mrD#.1HZSp\<TrRor$üĲ

1Ľ¡Ý%ŋů"Ĉ¥
%"


°Ű

ď#,!0â$¥áãĝ1 Pd ō¼¡Ý5ĆĚ1ķŖ5ûŏ

@[Clmr$¥á5Áá#Ë

#

26

OR

RO
O

O

RO
OR

RO

RO

36: R = Me
Ricarrdin C (3): R = H

37: R = Me
Cavicularin (2): R = H

Table 3-2 Previous studies on oxidative coupling of 36 and 3 in our laboratory.
entry

R

oxidant

conditions

time

results

1

Me

PIFA

BF3sEt2O, MeCN, −40 °C

10 mincomplex mixture

2

Me

PIFA

BF3sEt2O, CH2Cl2, −78 °C

40 mincomplex mixture

3

Me

PIFA

CF3CH2OH

30 mincomplex mixture

4

Me

VOF3

 TFA, CH2Cl2, 0 °C

120 minno reaction 

5

H

PIFA

CH2Cl2, −30°C

90 mincomplex mixture

į~ı ¥áŎě î#ĭú@[Clmr (2) $¥áŎě5 Fig. 3-4 #ĨÍ$¥áãĝ ¦ý
# 2 $HZSp\<TrRorüř%¥á$Ķġ"HZSp\<TrRorüř$üĲ#% Pd ō¼ Ar−Ar @O^mrD¡Ý5ŞĚ1

#@[Clmr#¾±1 2 īų$[\<Unĸ¥5¡ÝÞ#È* Pd ō¼¡ÝØá1 ŸÓ#Ā)$

@[Clmrŷù5ĕğ#¥á1Ŏě1Pd ō¼

Ar−Ar @O^mrD¡Ý$¡Ý³Ŕ

"1WpEr

4 $ļşåğ"WpEr#.0Æò#őŊ£Ŀ

HO
O C

OH



OMe

OMe

O

O

Pd-catalyzed
Ar− Ar coupling
reaction

10'

D
HO

Ľ

%8IPomr¥á$|Ū

MeO

D

X

Halogenation
at 10'-position

10'

MeO

HO

(±)-Cavicularin (2)HO
4

Fig. 3-4 Retrosynthetic analysis of (±)-cavicularin (2).
27įvı ½ Ar−Ar @O^mrD#.1HZSp\<TrRor$üĲ (±)-@[Clmr$¥á ó#¥ē 4 #É1 10’$ļşåğWpEr5ûŏ (Table 3-3)
(
4 5Ţţč¼|ŁĴĖ139

2H]ph38Ģğ 1]ph20%$¢ĕęá (Entry 1)

Û/2

42)

14’,ŁĴuï8KRURmn| N-]phICG:eS5Ě¡Ý5 "µ¥#%38 5 81%$Ÿ¢ĕz 1
 (Entry 2) 43)(Ũ¡Ý

4;Ĵ#,ûŏm;f

3gMVtn|k;TRm;f¾±xĂţTRÿ¶ĴţTRm;f5Ě1 (Entry 4)

1

44)

"1 Pd ō¼¡Ý$¡ÝÞ5Ľàk


OMe

OMe

OMe

O

O

O

X

10'

Br

MeO

MeO
HO

40 5Û

Áė"ļşåÞktS

MeO
HO

14'

HO

38: X = Br
40: X = I

4

Br

39

Table 3-3 Regioselective halogenation at C-10’.
entry

conditions

products

1

Br2, AcOH

38 (29%), 39 (20%)

2

NBS, MeCN

38 (81%)

3

NaBr, NaOCl, NaOH, MeOH

38 (60%)4

NaI, NaOCl, NaOH, MeOH

40 (75%) /#Pd ō¼$ţğ#É1¡ÝÞ$§w5Ģğ#ktS

40 $\<VtnÞĂţ³5 THF č¼| DMAP ō¼xĐĂŢţ8KNn 41 'ŐËŨ¡Ý
"1 Pd ō¼ Ar−Ar @O^mrD¡Ý5ûŏ (Fig. 3-5)
OMe

OMe

O

O
I

Ac2O, DMAP
THF, 97%

MeO

I
MeO

HO

AcO
41

40

Fig. 3-5 Acetylation of 40.
 (DMF č¼|ō¼ŢţYlH;f¶³ĎţŦ5Ěī$š½5Ě Ar−Ar @O^mrD¡Ý$ûŏ5Ňó#uńğ#Ÿ¡28

ÝÞ5Ĩ (o-tol)3P& t-Bu3P 5š½śŇ¥ē 43$)Ě¡Ý5Ň3ŀk;Ĵęá (Entries 1, 2)2% 0  PdţğÚPdC Ę#š1ÎŸ\>I\9rmArSĘ¡Ýś(¡Ý

ŀk;Ĵ

ğ#Ì n-Bu3P 5Ě$Ūę1ÖĭśŇ¡Ğ#.0

êċÿ#ĭ
1 Ar−Ar @O^mrD¡Ý3}ßŘ0ĢğśŇ@[Clmrŷù5ô1 42 5 39%$¢ĕÛ1 (Entry 3) 

ğ#Ì"š½1 Et3P 5Ěµ¥%Õű½zÞ

/#ĭ

Þ$+

$Ę¡Ý%śŇ"&yÀÃ (Entry 6)(d:Cp;<t]Ē

Ê-~Ôš½$ Dppe 5Ě¡Ý5Ňęáē 43¸Û/2¢ĕ$ì®#%ł/" (Entries 5, 7)óÚ#¡Ý÷$óŞ5Ň$Ť5 40 mol %/ 20 mol %#ĊŤ13n-Bu3P

 42 5 50%$¢ĕÛ1#á(Entry 4) 45)
OMe

C

O

Table

I

20 mol% Pd(OAc) 2
Ag2CO 3, DMF
120 °C

D

MeO

OMe

MeO
O

O

AcO

MeO
OAc

MeO

AcO

42

41

43

Table 3-4 Intramolecular Pd-catalyzed Ar−Ar coupling reaction of 41.
entry

ligandmol % of L

42 (%)

43 (%)

1(o-tol)3P

40

−

81

2

t-Bu3P

40

−

78

3

n-Bu3P

40

39

36

4

n-Bu3P

20

50

31

a

n-Bu3P

20

40

44

6

Et3P

40

−

−

7

Dppe

20

41

43

5

a

Using microwave (300W, 150 °C, 2 min).

 Fig. 3-6 #% Pd ō¼ Ar−Ar @O^mrD¡Ý$£Ŀ"¡Ýg@UJf5Ĩ 46)Ę# 2 $ţĴÂĿ³5ô1$³Ŕ% 3 īų$¡ÝþüĽ

/21uĢ%Č¨õ−Heck M:^$@nbYlQtGjr#.1ķŖ~Ģ%ţğÚ$ 2
YlH;f#É1ăű½ļë¡Ý5ķ1g@UJf1/#,ţğ#.0ę-Pd ŧor5Øá1ķŖ!$ķŖ¡ÝĢğĽuģé C−H ĸ¥5ĆÞHZSp\<TrR/21¯$¡Ýĳ%_rLrĘw$ű½ÇÓ

śŇ1



%ñ/

%"

1@[Clmrŷù$üĲ#á29

Ÿ

2#.ö¡Ý5Ň



Carbopalladation
MeO
O
41

Oxidative
Addition

X

MeO
O
XPd

Pd

MeO

MeO

AcO

AcO
CarbopalladationX
Pd OMe

OMe
O
42

O

H

– H+

– PdX

MeO

H
MeO

AcO

AcO

Electrophilic Substitution
MeO
O
41

Oxidative
Addition

X

MeO
O

Pd
X Pd

MeO
MeO

AcO

AcO
Electrophilic
Substitution

MeO
O

Reductive
Elimination

O

Deprotonation

Pd

42

MeO

X

H

MeO

Pd

MeO

AcO

AcO
C-H Activation

41

Oxidative
Addition

MeO

MeO

O

O
H
X Pd

X

Pd

MeO

MeO
AcO

AcO
C-H Activation

– HX
MeO
O

42

Reductive Elimination

Pd
MeO
AcO
Ligands are not shown.

Fig. 3-6 Plausible mechanisms of Pd-catalyzed Ar−Ar coupling reaction.
30 óÚ#Û/2 42 5gMVtn|Ďţ@m;f5Ě8KNn³5č¼ŌÚvŁa;ĴĖgNn³5Ŭ 20 āŭ 3.8%$Ļ¢ĕ@[Clmr (2) $lKe
ē$ 1H
tM

¥á5ŝá (Fig. 3-7)Fig. 3-8& 13C NMR I`CRn5Ĩ& Table 3-5 #¥á«¥á«$ NMR I`CRn%ºđē$QÁ"uŃ5Ĩ 12)
MeO
O

MeO
O

HO
O
BBr 3

K 2CO 3
MeOH, r.t.
OAc

MeO

OH

MeO

42

ºđ

CH2Cl271%
over 2 steps

HO

OH(±)-Cavicularin (2)Total 20 steps
3.8% over all yield

32

Fig. 3-7 Completion of the synthesis of (±)-cavicularin (2).
Natural
1MHz(600
MHz in CDCl )!!!!!!!!!
1
Natural
(600
in 2
CDCl
!!!!!!!!!!!!!
H NMR2 of
Natural(600)MHz in CDCl3) 3
3Synthetic
1 (500 MHz in CDCl3)!!!!!

1H NMR of Synthetic 2 (500 MHz in CDCl )
Synthetic 2 (500 MHz in CDCl3)
3

13 C NMR of Natural 2 (150 MHz in CDCl )3

13 C NMR of Synthetic 2 (125 MHz in CDCl )3

Fig. 3-8 Comparison of 1H and 13C NMR between natural and synthetic cavicularins.
31

2

1

4

5

3

7
10

HO 1' 6'
O
6

2'

8

11'

9

14

3'

12'

HO 11 12 13

5'
7'

4'
10'

8'
9'
14'

13'

OH

Cavicularin (2)Table 3-5 Comparison of 1H and 13C NMR between natural and synthetic cavicularinsa.
Naturalb 

position

1
2
3
4
5
6

6.10, dd (2,7 8.6)
6.46, dd (2.2, 8.6)

7

2.55, ddd (4.4, 13.4, 17.6)
2.96, m38.12.55, ddd (3.5, 12.5, 14.0)
2.92−2.98, m

38.1

8

2.28, ddd (4.4, 13.4, 17.6)
2.94, m37.42.28, ddd (3.5, 12.5, 14.0)
2.92−2.98, m

37.4

9
10
11

6.88, d (2.7)

141.6
116.9
155.5

6.88, d (2.5)

141.6
116.9
155.5

12

6.70, dd (2.7, 8.3)

114.7

6.72, dd (2.5, 8.5)

114.7

13

6.82, d (8.3)

131.6

6.83, d (8.5)

131.7

δH (600 MHz)

6.15, dd (2.2, 8.3)
6.71, dd (2.7, 8.3)

14
11-OH
1'
2'
3'
4'
5'
6'
1’-OH
7'
8'
9'
10'
11'
12'
13'
14'
13’-OHaδC (150 MHz)

153.8
115.1
127.8
135.0
130.0
117.8

SyntheticδH (500 MHz)

6.10, dd (2,5 8.5)
6.47, dd (2.5, 8.5)
6.15, dd (2.5, 8.5)
6.76, dd (2.5, 8.5)

128.9

2.66, m
2.76, m
2.66, m

6.40, s

6.68, s
4.75, s

153.8
115.1
127.8
135.0
130.0
117.8

128.9

4.88, brs

6.98, d (8.1)
6.94, d (8.1)
6.12, sδC (125 MHz)4.85, s147.8
138.5
123.3
131.7
123.0
113.0

6.98, d (8.0)
6.94, d (8.0)
6.12, s147.9
138.5
123.3
131.7
123.0
113.0

30.2

2.63−2.78, m

30.2

30.5
140.5
124.0
131.1
124.0
150.2
113.2

2.63−2.78, m

30.5
140.5
124.0
131.1
124.0
150.2
113.3

6.40, sIn CDCl3.
32

6.68, s
4.75, sŅÁń E_Iopt(zý¸õŅvŇ¸õŨı
 E_Iopt (2) (oPi¸õØ~#(#Ĕ' (+)-2 (zý¸õ;đũzý¸õ;ƈÒ7'v

6ŵzý;£í7 2 ŁƓ(¸õöĴ;ŃĐĺ)oPi(¸õŏŴ;(..¢įM^XsaAYtWrt(Ēňą'GoqƂÔ;į7$# (+)-E_Iopt(ŵzý;£í7ŏŴ#ĺ)

7

51M^XsaAYtWrt;¸õ"ćë'GoqƂÔ;

į7BYtSDƀøķƇĊ−ÜĜ´ï;ş

ŵzý$Ï¾ĭ;¹ą'Ēň7ŏŴ#

7 (Fig. 4-1)%5(öĴ2ŵzý(ĒňĚ$"8.#'É»(& ś

¼ĝ

¸õöĴ$

7

HO
Enantioselective
Pd-catalyzed Ar−Ar coupling
reactionO

Enantioselective
Suzuki−Miyaura reaction
HO
HO(+)-Cavicularin (2)• Enantioselective Pd-catalyzed Ar− Ar coupling reaction

OMe
O

MeO
O
*L
* L PdI

Pd-catalyst
withchiral ligand

I
MeO

HO
O
HO

MeO

HO

AcO

AcO

41

* L: Chiral ligand

2• Enantioselective Suzuki−Miyaura reactionHO

Pd-catalyst
withchiral ligand

O
HO

HO

HO

O

O

HO
B O
O

TfO

*L

OH

Pd

HO

* L OH* L: Chiral ligand

Fig. 4-1 Construction of axial chirality of (+)-cavicularin (2).
33

HO
2



ŅŇBYtSDƀøķÔ Ar−Ar ETcptJ´ï .BYtSDƀøķÔ Ar−Ar ETcptJ´ï;đũ(¸õĚ#)oPi¸õ(ŏŴ;(..įM^XsaAYtWrt(Ēňą'Goq
7 (Fig. 4-2)

ƂÔ;į7$#ŵzý;£í7Ũı#
OMe

HO

O

Enatioselective
Pd-catalyzed Ar− Ar coupling
reaction

I

O
HO

MeO

HO
AcO
41

2

Fig. 4-2 Enantioselective Pd-catalyzed ArAr coupling reaction.
 2 (oPi¸õ'" Ar−Ar ETcptJ´ï(´ïČ)ĽŃ#"#´ïÈŲ$&7nuX 41 'Þ"ƂÔ;GoqpFtX'

7(

´ï;ş

 (Table 4-1)?itÇ(GoqƂÔ A ;įÊ¸´ï)ż.&aCNa<?WÇƂÔ B ³+aCNa>tÇƂÔ;į
7 42 ;{

7$µĪ#)

7$: (Entries 1-4)ÂđũGoqƂÔ' "2Ńķ'à&ƂÔĘŶķŜ

Chiraphos ;įÊ¸'µĪŐď;{23Ɨ11Ɨee #ĭ® 42 ì58 (Entry 5)
OMe

MeO

DMF
120 °CMeO

OO

10 mol % Pd(OAc) 2
3 eq Ag2CO 3

I

OMe

MeO

O

MeO

AcO

AcO

AcO

41

42

43

Table 4-1 Enantioselective Pd-catalyzed Ar−Ar coupling reaction.
entry

ligandmol % of L

42

43

eea

1

A

10

−

−

−

2

B

10

7

−

7

3

(R,R)-Me-BPE

10

12

−

6

4

(S)-BINAP

10

18

−

7

5

(S,S)-Chiraphos

10

23

−

11

aEes were determined by HPLC.

O
Bn

N

N
A

Me

O

O

O

Bn
B

P N

P

PPh 2

P

PPh 2

Me
Me-BPE

34

BINAP

Ph 2P

PPh 2

Chiraphos ċ´ï#)BYtSDƀøñòx'1(±Ã;ă5

'7ĺķ#GoqEoj;į HPLC Ď;ş (Fig. 4-3)(ŐďnuX 41 #'ŵzý;ĈoPi#oPi#

ă&:´ïÈŲ

71'BYtSDŽ§Ī&$ŕċ´ï)ĬŮµĪ'ƋĲ
ƐÄƑ#

7$

7'«

"ĮõĨ#

587($5

7BYtSDhuĞ¸Ĩ(7$5(ėƍ#(zýß;ÿð2v(¸õŏŴ;đ

ũ7$'

MeO
O
3'

MeO

MeO

O

O

1) NaI, NaOH, NaOCl
MeOH, 75%I10'2) Ac2O, DMAP
THF, 97%

MeO

MeO

I
+

MeO
AcO

AcO

HO

41a

4

41b

HO

HO

O

O

HO

HO
HO
(+)-2

HO
(−)-2

Column : 4.6 x 150 mm, Kromasil 3-CelluCoat
Solvent : Hex : i-PrOH
Flow rate : 1 mL/min
41a and 41b
Detector : UV 254 nm

Column : 4.6 x 150 mm, Kromasil 3-CelluCoat
Solvent : Hex : i-PrOH
Flow rate : 1 mL/min
4
Detector : UV 254 nm

Fig.4-3 HPLC analysis of 4 and 41 using chiral column.

35ŅwŇ BYtSDƀøķƇĊ−ÜĜ´ï GoqƂÔ;į7BYtSDƀøķƇĊ−ÜĜ´ï'47E_Iopt(ŵzý(ĒňĚ;đũ7$' (Fig. 4-5)&:

51 Pd ŧÓÔ

Ar−Ar ETcptJ´ï#M^XsaAYtWrt;éõ"¸õŎĹ#BYt
SDƀøķƇĊ−ÜĜ´ï;&
$

2(#

MeO
BnO

C
Br

$'46Ï¾ĭ$ŵzý;vù'Ēň77

Pd catalyzed
Ar− Ar coupling
reaction

MeO

A

MeO

C

O

B

D

B O
O

MOMO
OMe
44

D

TfO

HO

Enatioselective
Suzuki−Miyaura
reaction

O
HO

OMe

HO

45

(+)-Cavicularin (2)Fig. 4-5 Enantioselective Suzuki−Miyaura reaction.
 8.#(¸õöĴ;ïįBYtSDƀøķƇĊ−ÜĜ´ï(ÈŲ¸õ;&.]Zpt;Ķ±þ$"MIsskRtĢÓ| N,N-M?Qcs`qB
Sq=itÕÆyaA\uqñęƄÈ; MOM È#ůD ĭmZTW 46 ;vėƍ95%(µĪ#ŭŢ (Fig. 4-6)

CHO

CHO
MOMCl, DIPEA

OMe
OH

D
OMe
OMOM

CH2Cl2
95%

46

VanilinFig. 4-6 Preparation of unit 46.
 Ĕ'?Q]Zpt;ƃƄĢÓ|Ŕƀøķ'řō®bsl 47 $( 47)aA\uqñęƄÈ;dtMqÈ#ů 48 ;ì48 (=qV^X;ęō®e@ōY
Wp@j'46dtMq=qKuq,Ɓëì58=qKuq;MIsskRt
ĢÓ|Ářō®ģō³+WpaAZqaCNa>t#Ĭř®dtMq 50 ,Íûćë'WpkSqaCNa<?W;į

 Michaelis−Arbuzov ´ï'46 C ĭmZ

TW$&7eNe[uW 51 ;ŭŢ (Fig. 4-7)
36

CHO

CHO
Br

Fe powder, Br 2
NaOAc

OH
OMe

BnBr, K 2CO 3

OH
OMe

HOAc
71%

CHO
Br
OBn
OMe

DMF
91%

47

Isovanilin

48
NaBH 4
THF, 99%

O
P(OMe) 2
Br

C
OBn
OMe

Br

OH

P(OMe) 3

Br

CBr 4, PPh 3

BrBenzene
98%

OBn
OMe

CH2Cl2
85%

OBn
OMe

50

51

49

Fig. 4-7 Preparation of unit 51.
 Ĕ'D ĭmZTW46$C ĭmZTW51; HWE ´ï46ŻŐëNSqdt(Dra>t;^XoMtƁC−D ĭmZTW44,ß  (Fig. 4-8)

D
OMe
OMOM
46

MeO

O
P(OMe) 2

CHO

+

Br

C
OBn
OMe

MeO
NaH
THF
93%

TsNHNH2, NaHCO 3

BnO
Br

51

EtOC 2H 4OH
79%

OMOM
OMe

BnO
Br
MOMO
OMe
44

52

Fig. 4-8 Preparation of 44.
 ì58 44 'Þ" Pd ŧÓ Ar−Ar ETcptJ'47M^XsaAYtWrt¸õ;đũ (Table 4-2).oPi¸õ#įČ;žį´ï;ş$9ĺķĨ 53  9Ɨ(µĪ#ì582((Î(±þÂµ8 (Entry 1)
(Č#)´ï(żşŸ|#ĕ$5ŧÓ(Ŧľ¿8#ƂÔ; 60 mol%.#ėƍķ'ÌƆ´ï;&$940 mol%( n-Bu3P;įÊ¸'µĪ 23Ɨ±þÂµ;ŕôµĪ 59%.#µĪºx (Entry2)Ĕ'ËÈ;đũŐďģƄEp@j;į

7$´ïØŐ7$:6

ĺķĨ 53 ; 32%Ŕĵñ 54 ; 52%(µĪ#ì (Entry 4)C-H ěñ®´ï;ż7`]s?qƄ(ğ«3ËÈ; CsOPiv 'ÍĆ"2 54 (Ì«3ŗbsl 55 (Įõ;÷7$)#µĪ) 10−20%'ĳ. (Entries 5, 6).ĢÓ­ď3ƂÔ(ŁƓ;ÍĆē&´ïČ;Ū/¦ĮõĨÌ«7(/#ŜÑ&Őď;ì7)č& (Entries 7-13)(ėƍ'±þ(Âµ¶Ŗ& Entry 2 (Č#´ï;ş
37"µĪ(üÀ')Ś5&¸õ;'ż17$'

MeO

MeO

MeO

20 mol % Pd cat.
3 eq Base

BnO

BnO
MeO

BnO

Solvent(0.01 M)
120 °C

MOMO

MOMO

MOMO

MeO
BnO
Br
MOMO
OMe

OMe
53

44

OMe
54

55

Table 4-2 Intramolecular Pd-catalyzed Ar−Ar coupling reaction of 44.
entry

Pd

ligand

mol %

base

solvent additive 44

1
Pd(OAc)2 n-Bu3P
20 Ag2CO3 DMF−
2
Pd(OAc)2 n-Bu3P
40 Ag2CO3 DMF−
3Pd(OAc)2 n-Bu3P
60 Ag2CO3 DMF−
4
Pd(OAc)2 n-Bu3P
40
K2CO3 DMF−
5
Pd(OAc)2 n-Bu3P
40
K2CO3 DMF PivOH
6
Pd(OAc)2 n-Bu3P
40 CsOPiv DMF−
a7
Pd(OAc)2 n-Bu3P
40 Ag2CO3 THF−
b
8
Pd(OAc)2 n-Bu3P
40 Ag2CO3 Dioxane−c9
Pd(OAc)2 n-Bu3P
40 Ag2CO3 Toluene−
10 Pd(OAc)2 n-Bu3P
40 Ag2CO3 DMSO−
11 Pd(OAc)2 (o-tol)3P 40 Ag2CO3 DMF−
12 Pd(OAc)2
Cy3P
40 Ag2CO3 DMF−
13 Pd(PPh3)4−−
Ag2CO3 DMF
−
a
b
c
d
60 °C, 100 °C, 110 °C, Based on recovered starting material.

65
61
60
−
−
−
−
−
−
−
32
18
12

53

54

55

borsmd
53

9
23
22
32
17
11
20
−
−
26
12
30
11

12
15
11
53
43
25
2
−
−
55
6
39
19

−
−
−
−
19
43
59
67
94
14
−
−
−

26
59
55
−
−
−
−
−
−
−
25
38
13

 Ĕ'53 5Ïĭĩĭ®¤ƕ$&7 45 ,(Ŭß;& (Fig. 4-9).
úŧƁ'46 53 (dtMqÈ;ƌ² 56 ; 97%(µĪ#ì56 $ p-bsldt
O=qV^X$( Ullmann ´ï'46 A ĭ;ŻŐëB ĭmZTW 7 $( HWE ´ï'46"(ŝƔĭ; 58 ;°v®¸Ĩ$"ŭŢŒ^XoMt'47N

Sqdt(Ɓ4+ƄñČy#( MOM È(ƌ²;ŻŒķ'&aA\uq 60 ,ß ćë'ÜĜ´ï'47fstƄBNUq(ßëęƄÈ;Wpar
uW,Íû7$# 45 (ŭŢ;Ø~ (Fig. 4-9)

38

MeO

MeO

BnO

H 2, Pd(OH) 2

MOMO

CHCl 3
97%

HO

A
O

Pyridine
65%

MOMO

OMe

MeO

OHC

p-Bromobenzaldehyde
CuO, K 2CO 3

MOMO

OMe

OMe

56

53

57

OMe
O
P(OMe) 2

B
Br

7

OMe

OMe
MeO

Dowex ® 50WX2−100
MeOH/EtOAc= 2: 1
70 °C
96%

NaH
THF, 97%

Br

B

O

TsNHNH2, NaHCO 3

MeO
A

Br

O

EtOC 2H 4OH
98%

MOMO
OMe

MOMO
OMe

59

58

OMe

OMe
Pd(PPh 3)4
B 2Pin 2
K 3PO 4MeO
Br

O

Dioxane
95%

HO

OMe
MeO

B
O

O

O

MeO

PhNTf 2Cs2CO 3
THF
77%

B
O

O

O

HO

OMe

TfO

OMe

60

OMe
45

61

Fig. 4-9 Preparation of boronate 45.
 "ŭŢ 45 'Þ"BYtSDƀøķƇĊ−ÜĜ´ï'47Ï¾ĭĒň;đũ (Table 4-3).=Goq&ƂÔ#

7 SPhos ;į"ƇĊ−ÜĜ´ï;&$9ĉ0ĭ®´ïżş 25Ɨ(µĪ#ĺķĨ 37 ;ì7$#(Entry 1)8'46 45 'Þ7Ï¾ĭĒň¶Ŗ#

7$;Ľū#(#(Č;È'GoqƂÔ;įBYtSDƀøķƇĊ−ÜĜ´ï;Ū/ć'GoqƂÔ$" (S,S)-Chiraphos ;į

´ï;ş$9´ï)żş

±þ;Âµ7'ĳ. (Entry 2)vāƂÔ; (R,S)-PPFA 'ÍĆ$9
µĪ 3%9%ee (BYtSDƀøñ# 37 ;{(S)-(−)-BINAP ;įÊ¸')BYtSDƀøñ'Í®)ť58&2((µĪ 12%.#ºx (Entries 3, 4)
Ĕ'ƂÔ; BINAP 'ÅÙËÈĢÓ³+ Pd ŧÓ;đũ (Entries 5-13)
(ŐďËÈ;ptƄEp@j'ÍĆ7$#BYtSDƀøñ; 18%ee .#ü
À7$# (Entry 9)
ŗWparuW®}´ï$&6ġų®´ï'"´ïĤƐ8"

8(´ïČ2µĪÎ(Ê¸Őď;ì7$)#&8)ĭ

7$5'éõ87Ï¾ĭƖæ&Ė/;39Ĉ7$'46ĭ®´ï(ěñ®B[qHuÏƇĊÜĜ´ï(´ïźæŞ&"

7$±Ã$ŕ

587

OMe

OMe
MeO

MeO
B
O

10 mol % Pd cat.
20 mol % Ligand
3 eq BaseOO

Solvent (0.001 M)
100 °C

TfO

MeO

O
B
O

MeO

O

O

MeO

OMe

OMe

45

37

62

Table 4-3 Intramolecular Suzuki−Miyaura reaction of 45.

a

entry

catalyst

ligandbase

solvent

45

37

62

eea

1

Pd2(dba)3SPhos

Na2CO3

DMF

9

25

15

−

2

Pd2(dba)3(S,S)-Chiraphos

Na2CO3

DMF

60

−

−

−

3

Pd2(dba)3(R,S)-PPFA

Na2CO3

DMF

40

3

−

9

4

Pd2(dba)3(S)-(−)-BINAP

Na2CO3

DMF

36

12

−

9

5

Pd2(dba)3(S)-(−)-BINAP

Na2CO3 Dioxane

70

−

−

−

6

Pd2(dba)3(S)-(−)-BINAP

Na2CO3 Toluene

86

−

−

−

7

Pd2(dba)3(S)-(−)-BINAP

Na2CO3

DMSO

−

3

−

6

8

Pd2(dba)3(S)-(−)-BINAP

Ag2CO4

DMF

62

−

−

−

9

Pd2(dba)3(S)-(−)-BINAP

K3PO4

DMF

60

2

−

18

10

Pd2(dba)3(S)-(−)-BINAP

Tl2CO3

DMF

19

4

−

5

11

Pd(OAc)2(S)-(−)-BINAP

K3PO4

DMF

−

trace

18

2

12

Pd(dppf)Cl2(S)-(−)-BINAP

K3PO4

DMF

11

trace

58

0.4

Ees were determined by chiral HPLC.

ŅÁŇ zýš¬È;į

7 Ar−Ar ETcptJ´ï BYtSDƀøķ Ar−Ar ETcptJ´ï$ƇĊ−ÜĜ´ï#)µĪ³+BYtSDƀøñ¯&Őď;ì7$#(+)-2 (ŵzý;£í7Ā&¸õöĴîŤ$&èļłÛ#&"_N_dtMqƓ(¸õļł)Į¸õŏŴ'È!

­Īķŉ&¸õöĴ#6(+)-2 (zý¸õ'

gpLu;ű¸õŏŴ;đũ7$'ŅŇ#ŷ-4"2('nuX 41)n@ōßą'ŵzý;Į71BYtSDƀøķn@ō®´ï#8*(+)-2 (zý¸õ¶Ŗ'&7īÆ(4&´ï)ĸĥ#£ŋ5¡Ě'47zýß;đũ7$'zýßĚ')ē
Ķ8"7ć2ŉ&āĚ( 16ąƉķ&&āĚƈ

$"zýš¬È;¢į7M=NUrDƀ
40

øķ&zýĒňĚù587zýš¬È;¢į7$'46Ń®Ö;£í
3.¦ĮõĨ)ĺķĨ$M=NUrDhu(Ɗ'&7$#ŊŢÝĄ'&6ćŎķ'Ɩ

BYtSDŌæ;2ĺķĨ(¸õ¶Ŗ#

7#D ĭx( 13’ęƄÈ'ÝĄ'ŗĻ¶Ŗ&zýš¬È;ßM=NUrDƀøķ'M^X
saAYtWrtĭ;Ēň7Ũı;Ń" (Fig. 4-10)&:zýš¬È;ß´ïÈŲ'Þ"8.#'ĽŃ Pd ŧÓ Ar−Ar ETcptJ´ï;ş ŉ­Īķ& (+)-E_Iopt (2) (¸õ;ş

āĚ#

7

Enantioselective reactions• Pd-catalyzed Ar− Ar coupling reaction
OMe
MeO

O
10 mol % Pd(OAc) 2
10 mol % (S,S)-Chiraphos
Ag2CO 3

I

MeO

DMF
120 °C
23%, 11%ee

MeO
AcO

O

AcO

42

41

• Suzuki−Miyaura reaction

OMe
MeO

MeO
B
O

10 mol % Pd 2(dba) 3
20 mol % (S)-(−)-BINAP
3 eq K 3PO 4

O

O

TfO
OMe

O
MeO

DMF (0.001 M)
2%, 18%ee
100 °C

MeO
37

45

Diastereoselective reaction• Pd-catalyzed Ar− Ar coupling reaction

MeO
OMe
O

I

Pd catalyst

O
Pd

I

HO
MeO

MeO

∗ RO

HO

O

∗ RO

HO

13'

∗ R = Chiral auxiliary∗ R = Chiral auxiliary2

Fig. 4-10 Construction of axial chirality of (+)-cavicularin (2) using chiral auxiliary.
41 zýš¬È(ß'6Ũņ®Ö;¢įćž&zýš¬È;ƀø (Fig.

4-11)48)M=NUrDƀøķ&´ï#)M=NUrDhuƉ#´ï(ſĿĩó(B[qHuáÏ&7zýš¬È;į$'ć2Ŝ#ƀøñì587)7ſĿĩó(Ũņ)ţƏ#ŘÏ&ąƉîŤ'&6īÚķ&āĚ#)&#ĮõĨ(B[qHuá;Ũņ7$'ŹäĮõĨ(ħ©

Ö×Ùñ)åŠ´ï'"Ĉį#7Â)ŨņÝĄ#ċ´ï#) Pd (Ƅ®ķ«ë(ĭéõêźėƍ#õĨ(B[qHuáƅŤ#

7$7$Ġ87$5ĮÿŨņ;şzýš¬È(š®¸Ĩ$"âŰ( Fig. 4-11 'ľ 6 ŁƓ(GoqEqftƄ;ßBNUq'

7$.

·

;E_Iopt'"ć×ÙƂç;ŦĎB[qHuŨņ;ş(ŐďÎ(BNUq#)B[qHuá 1 5 3 kJ/mol $à('Þ(S)-(+)YcsGPt;ß®¸Ĩ 64 #) 13 kJ/mol $&6B[qHuáÏ&7ăåŠĩó$ÙÊ¸( Boltzmann ã2 99.5 : 0.5

$

x$ƒä'Ɩ

(ŨņŐď5zýš¬È$" (S)-(+)-YcsGPt;į 7Őď;{$'OH
O

I

Diastereoselective
Pd-catalyzed
Ar− Ar coupling
reaction

HO

HO

O

O

HO

HO

HO

O

MeO

* RO
* 63: R = Chiral ester

O

>>

0.5

O

OMe

O

HO
F 3C

HO

O
O

OMe

(S)-MTPA
S : R = 46.0 : 54.0
ΔE = E S −ER = −1.51 kJ/mol(S)-(+)-Naproxen
S : R = 99.5 : 0.5
ΔE = E S −ER = 13.18 kJ/mol

OH(1S)-(−)-Camphanic acid
S : R = 75.9 : 24.1
ΔE = E S −ER = 2.85 kJ/mol

O

O
HO

O
(R)-Naproxen-64(S)-Naproxen-64

99.5

O

O
MeO

O

O

HO
Me

O
(S)-1,4-Benzodioxane-2-carboxylic acid
S : R = 64.8 : 35.2
ΔE = E S −ER = 1.51 kJ/mol

HO
OMe(S)-(+)-MαNP acid
S : R = 52.6 : 47.4
ΔE = E S −ER = 1.09 kJ/mol

Fig. 4-11 Selection of chiral auxiliary.

42

O(−)-Menthyloxyacetic acid
S : R = 78.5 : 21.5
ΔE = E S −ER = 3.22 kJ/mol .zýš¬È;ß´ïÈŲ(ŭŢ;ş (Fig. 4-12)oPi®¸Ĩ#7bsl 38 $nuX 40 'Þ"MIsskRtĢÓ| EDC ;œ¸¥$"į"zýš¬È (S)-(+)-YcsGPt$œ¸(´ï#)BYtSDhuƉ#(´ïñ'á)&ŋ 1 : 1 (M=NUrDhuĞ¸Ĩ 65 ³+ 66 88 78%4+ 68%(µĪ#ì58
OMe

OMe

O

O
(S)-(+)-Naproxen
EDC, DMAPX

X
CH2Cl2

MeO

MeO

HO

O
MeO

O

Racemates

Diastereomeric mixtures

38: X = Br
40: X = I

65: X = Br (78%)
66: X = I (68%)

Fig. 4-12 Preparation of 65 and 66.
 (bsl 65 ³+nuX 66 'Þ"M^XsaAYtWrtĭĒň;đũ (Table 4-4)#)M^XsaAYtWrtĭĒň'oMEq´ï$ Pd ŧÓ´ï;88žį´ï;ĘŶ(ŐďoMEq´ï#)´ï)żş72((67 $ 68 ŋ 1 : 1 5 3 : 2 (¨¸#ĮõM=NUrDhuƉ#(´ïñ'á)ū158& (Entries 1, 2)vāPd ŧÓ Ar−Ar ETcptJ´ï#)bsl
 65 #)±þ;Âµ7(/#nuX 66 'Þ"´ï;&Ê¸µĪ 78%ŋ 5 : 3 (ĮõĘ#M^XsaAYtWrt 67 $ 68 (Ğ¸Ĩ;ì7$'õª (Entries 3, 4)
OMe
O

X

MeO

MeO

O

O

Diastereoselective
Ar− Ar coupling
reaction

MeO

MeO

MeO
O

MeO

O

O

O

MeO

O

O

MeO
67
[α]D 25 = +30.0 (c = 0.500, CHCl 3)

65: X = Br
66: X = I

68[α]D 27 = −10.4 (c = 0.500, CHCl 3)

Table 4-4 Diastereoselective Ar−Ar coupling reaction of 65 and 66.
entry

X

conditions

SM

1

Br

HSi(SiMe3)3, AIBN, Na2HPO4, Benzene

38

56

1:1

2

I

HSi(SiMe3)3, AIBN, Na2HPO4, Benzene

-

48

3:2

3

Br

Pd(OAc)2, n-Bu3P, Ag2CO3, DMF

78

-

-

4

I

Pd(OAc)2, n-Bu3P, Ag2CO3, DMF

-

78

5:3

43

67 + 68 (%) ratio (67 : 68) nuX 66 'Þ7 Ar−Ar ETcptJ´ï#)´ïÈŲÂµ8" & $5Ƅ®ķ«Žŀ#)M=NUrDhuƉ#´ïñ& $ľ¿87
(1ŨņŐď'Ę-ÚƎ(ƀøñy$ŕ 587ĭéõėƍ'"ĮõĨ(B[qHuá'İč7ĭ®(´ïźæ'áĮ46×Ù#ĭéõ83 67 "ì58$ŕ  (Fig. 4-13)
MeO

MeO

O

O
I

MeO

Pd

+Pd(0)

O

fast

I

MeO

MeO

−Pd(0)

MeO

MeO
O

O

MeO

O

O

66a

67
MeO

MeO

O

O
I

MeO
MeO

O

MeO

O

I

+Pd(0)Pd

O

O−Pd(0)
MeO

MeO
O

MeO

slow

O

MeO

O

MeO

66b

O

O

68

Fig. 4-13. Difference of reactivity between diastereomers 66a and 66b.

ŅŇ (+)-E_Iopt(zý¸õ Ar−Ar ETcptJ´ï'46ì58 67 $ 68 (M=NUrDhuĞ¸Ĩ)Eoj
IshWJoa>u#ÝĄ'Ɛ7$#°Ɛ 67 (zýš¬È;ęō®
=qiZ@jpS@j#Ɓķ'ƌ²MkSqE_Iopt 32 ; 88%(µĪ#ì
ćë' 32 ;wřō®e@ō#ĬkSqÈ;ƌ²7$# (+)-E_Iopt(2) (¸õ;Ø~ (Fig. 4-14)¸õ 2 ) [α]D21 = +115.7 (Ăñ;ľÐĦĨ(Ăæ ([α]D20 = +168.2) $ĘŶ7$'46¸õ½ÐĦĨ$¹őÞŃƂ
Ŕ;Ĉ7 (+)-E_Iopt (2) #7$;Ľū 12)

44

MeO
O

SiO2 chromatography

Mixture of 67 and 68

MeO
O
MeO

O

67
[α]D 25= +30.0 (c = 0.500, CHCl 3)
LiAlH 4
THF, 0 °C
88%
HO

MeO

O

O
BBr 3

HO

CH2Cl2
72%

HO

MeO
HO

(+)-Cavicularin (2)32[α] D 22 = +117.2 (c = 0.767, CHCl 3)

20 = +168.2 (c = 0.25, MeOH)

Natural: [α] D
Synthetic : [α] D 21 = +115.7 (c = 0.700, MeOH)

Fig. 4-14 Completion of the synthesis of (+)-cavicularin (2).
 GoqEoj;į HPLC Ď(Őď¸õ½( (+)-2 )97.9%ee $Ɩ BYtSDŌæ#

7$;Ľū(+)-E_Iopt (2) (zý¸õ;Ø~ (Fig.

4-15)Column : 4.6 x 150 mm, Kromasil 3-CelluCoat
Solvent : Hex : i-PrOH
Flow rate : 1 mL/min
Detector : UV 254 nm
HO
O

OH

HO

(±)-Cavicularin (2)Column : 4.6 x 150 mm, Kromasil 3-CelluCoat
Solvent : Hex : i-PrOH
Flow rate : 1 mL/min
Detector : UV 254 nm
HO
O
HO
HO
(+)-Cavicularin (2)Fig. 4-15 HPLC analysis of cavicularin (2) using chiral column.
45I ©
 |©v¤£ni"-2B@D A (1) ['8)?@¸^s¬a^st!a­
D (2) ^s!

c8-8;D,A



 "-2B@D A (1) ^sc8-8;D,A¸zc_®!T
fS³{−j\q!  4 ksW

²Y'1:@

D*\q!~¨}&(+bY65,#= (V) !,;D/9?DN^s!´sW R 17 ¶ 6.4%] 1 UR^s!¯s



OMe
O

B

O

O

O

OMe

OH

OMe

O
1) Pd 2(dba) 3, SPhos
Na 2CO 3, DMF, 72%

MOMO

OTf

2) Dowex ® 50WX2-100
MeOH/EtOAc = 2:1
83%1) VOCl3, CH2Cl2
58%2) BBr 3, CH2Cl2
76%

MeO

HO
O
Asterelin A (1)Total 17 steps
6.4% over all yield

HO 13'
424 '8)?@D (2) ^s?.<M (±)-2 PgrM (+)-2 ^s·~¨?.<M^s 4  10’K!°u>#Y 41 k

TfS Ar−Ar '1:@D*\q!¥}Pd(OAc)2−nBu3P §e!

,74C9$5D3BD!R 20 ¶ 3.8%] 2 ?.<M^s
sW


O

OMe

1) NaI, NaOCl, NaOH
MeOH, 75%
2) Ac2O, DMAP
97%



¡

1) Pd(OAc) 2, n-Bu3P
Ag2CO 3, DMF
120 °C, 50%

I

10'

MeO

2) K 2CO 3, MeOH
3) BBr 3, CH2Cl 3
71% over 2 steps

MeO

HO

AcO

4

41

­Gw

°u Ar−Ar '1:@D*\q%5D0&°uTfS³{−j Ar−Ar '1:@D*\q!~¨\q][M°urL «
46

HO

OH

(±)-Cavicularin (2)Total 20 steps
3.8% over all yield(+)-2 Gw^s'8)?@Dzw¦Xa!V

HO
O

OMe

O

%5D0&\qG

}%5D0&°u}!p

Enantioselective Pd-catalyzed Ar− Ar coupling reaction
OMe
MeO

O

10 mol% Pd(OAc) 2
10 mol% (S,S)-Chiraphos
Ag2CO 3

I

O

MeO

DMF
120 °C
23%, 11%ee

MeO
AcO

AcO

42

41

Enantioselective Suzuki−Miyaura reaction
OMe
MeO

MeO
B
O

10 mol% Pd 2(dba) 3
20 mol% (S)-(−)-BINAP
3 eq K 3PO 4

O

O

O
MeO

DMF (0.001 M)
2%, 18%ee
100 °C

TfO
OMe

MeO

37

45

 Fx (S)-(+)-5:C(.D!Gw¦Xa Ar−Ar '1:@D*\q

lQ 78%]5 : 3 ,"-2B&°ur 67 !pw¦Xa²aOªa!µZ?@D (2) ^s!hH

R 20 ¶ 4.0%] (+)-'8)

|

J*AE:^s¯s 97.9%ee ¹%5D0&md`?@D (2) ^ssWyoGkM±¢!z (+)-'8)

Diastereoselective Pd-catalyzed Ar− Ar coupling reaction
OMe
O

MeO

MeO

O

O

Pd(OAc) 2, n-Bu3P
Ag2CO 3

I
MeO

MeO

DMF
78%
67 : 68 = 5 : 3

O
O

MeO

MeO
O

O

O

MeO

MeO

68

67

66

MeO

HO

O

O
1) LiAlH 4, THF
0 °C, 88%

MeO
O

MeO

O

2) BBr 3, CH2Cl2
71%

HO
HO

(+)-Cavicularin (2)

67

47

O



1) Kosho Makino, Kenichi Harada, Miwa Kubo, Hideaki Hioki, Yoshiyasu Fukuyama. Total
Synthesis of Bisbibenzyl Dibenzofuran Asterelin A via Intramolecular Oxidative Coupling.
Natural Product Communications, 8, 915−918 (2013). ()2) Kenichi Harada, Kosho Makino, Naoki Shima, Haruka Okuyama, Tomoyuki Esumi, Miwa
Kubo, Hideaki Hioki, Yoshinori Asakawa, Yoshiyasu Fukuyama. Total synthesis of riccardin C
and (±)-cavicularin via Pd-catalyzed Ar−Ar cross couplings. Tetrahedron, 69, 6959−6968(2013). ()

48

Đþ
Æ¶
 Ó«ÎĉÆĈ·Æ¶!Ø ²ßºrĒ (NMR) 4L,>YVarian àô Mercury-300 Mercury plus-300 
MR-400 MR-500 !Ø<>WS:Y2W\ (TMS) !sþµÇÆÆÈĂ,[[MYR (CDCl3) Ă"6>\ēacetone-d6Ĕ!Øy2H> (d)  ppm zhç© (J)  Hz zh÷ú2-@Y^Ăè seĂè d_Ăè t Ăè qĂè m ó÷mbr ó÷ ùè (IR) 4L,>Y¬¯vqàô FT/IR-4200 vqqö!Ø ATR½Æ øă (MS) P44L,>Y¬¯Ċàô JNM-AX 500 } The MStation JMS-700
đvõëøăv±ö!ØĊò§$)\y½ (EI)y$)\y½ (CI)đû|òâ$)\y½ (FAB) Æđû|òâ$)\y½ (FAB) P>X;,4 m-A>[K\3Y"Y/]Y!ØÆªÖb¶

6\9]kċČñ­ćP44L,>Y (TOF-MS)  PerSeptive Biosystems àô Voyager TM DE RP !ØÆ đûÂi,[P>-WH#] (HPLC) ¬¯vqàô PU-1587 !O\JØ³u  ¬ ¯ v q à ô UV-2075 ! Ø      Ã ¬¯vqàô

MX-2080-32 !ØHPLC Ø*WR@*W$<4,àô COSMOSIL 5SL-II(20×250 mm) !jØHPLC Ø+WY*WR Akzo Nobel àô Kromasil
3-CelluCoat (4.6×150 mm) !jØ )]J\*WRpw2X*.YĕĈ°yàô Silica gel 60N (ÕÔb¡)
63−210 µmqäð´àô Wakogel C-300 45−75µm Ĉ°yàô Silica gel 60N(ÕÔb¡) 40−50 µm !jØ vØv±ØïÚ,[P>-WH#] (TLC) MERCK àô Silica gel 60 F254
0.25 mm !jØ4O;>³u 254 nm  UV W\JÏV%åîºÜ
10% X\TXI=\ā'9B]YÙíw}Þāā¡ 2% "A4"Y=E?'9B]YÙíwÁxÐ





49

4-Benzyloxy-3-hydroxybenzaldehyde (12)CHO

CHO
BnBr, K 2CO 3Acetone, reflux
63%

OH
OH
11

OH
OBn
12

 3,4-3E?[+2K\5"Y=E? (11) (2.03 g, 14.7 mmol) "6>\ÈÂ (150mL) Íā*X%R (3.05 g, 22.1 mmol) ìyK\3Y (1.74 mL, 14.7 mmol) !x
65 °C4­ćxÐ×¿~ ædCelite®535RVSÌüÌÂ!Ëé ¹Ä!*WR,[P>-WH#] (Toluene:EtOAc = 13:1) ãô12 (2.12 g,
63%) !
Compound 12: colorless solid; 1HNMR (300 MHz, CDCl3): δ 5.21 (2H, s), 5.77 (1H, s), 7.05
(1H, d, J=8.2 Hz), 7.40−7.47 (7H, m), 9.86 (1H, s); 13C NMR (75 MHz, CDCl3): δ 71.3, 111.5,
114.4, 124.4, 127.9, 128.8, 128.9, 130.8, 135.2, 146.3, 150.9, 191.0; IR (ATR): 3201, 1672,
1604, 1577, 1511, 1454 cm−1; EIMS m/z (rel. int.): 228 [M]+ (40), 92 (40), 91 (100), 65 (40);
HR-EIMS: [M]+ calcd for C14H12O3 228.0786; found 228.0789; mp: 120.0−122.0 °C.
4-Benzyloxy-3-methoxymethoxybenzaldehyde (6)CHO

CHO
MOMCl, DIPEACH2Cl2, 0 °C
84%

OH
OBn
12

OMOM
OBn
6

 12 (2.60 g, 11.4 mmol)  CH2Cl2 ÈÂ (114 mL) ! 0 °C t{MOMCl (1.73 mL,
22.8 mmol)  DIPEA (3.98 mL, 22.8 mmol) !x 12 ­ć¨¤»!x~ !n¸»! CH2Cl2 £u®¶!»Ďč»¾ÀÞā@>X%RcÑËé ¹Ä!*WR,[P>-WH#] (Hexane:EtOAc = 3:1) ãô 6 (2.44 g, 84%) !Compound 6: yellow oil; 1H NMR (300 MHz, CDCl3): δ 3.50 (3H, s), 5.21 (2H, s), 5.25 (2H, s),
7.00 (1H, d, J=8.4 Hz), 7.36−7.47 (6H, m), 7.66 (1H, d, J=1.9 Hz), 9.80 (1H, s); 13C NMR (75MHz, CDCl3): δ 56.3, 70.6, 95.3, 113.0, 116.0, 126.6, 127.1, 128.1, 128.6, 130.1, 135.9, 147.1,
154.2, 190.6; IR (ATR): 2826, 1684, 1582, 1505, 1454, 1434 cm−1; EIMS m/z (rel. int.): 272[M]+ (78), 227 (35), 181 (40), 91 (100), 65 (40), 45 (80); HR-EIMS: [M]+ calcd for C16H16O4
272.1049; found 272.1041.
Dimethyl (2-bromo-5-methoxybenzyl)phosphonate (7)
Br
Br
OMe

P(OMe) 3

Br

reflux98%

O
P(OMe) 2

OMe
7

13

50

 2-I[T-5-S>+2K\3YI[Q? (13) (10.0 g, 35.7 mmol) fX\ā>XS:Y (13.0 mL, 107 mmol) ÃÒ! 90 °C  2 ­ćxÐý¿Ëé ¹
Ä!*WR,[P>-WH#] (EtOAc) ãô 7 (10.8 g, 98 %) !Compound 7: yellow oil; 1H NMR (300 MHz, CDCl3): δ 3.39 (2H, d, J=22.1 Hz), 3.70 (3H, s),
3.74 (3H, s), 3.79 (3H, s), 6.68 (1H, dd, J=2.9, 8.8 Hz), 7.00 (1H, d, J=2.9 Hz), 7.44 (1H, d,
J=8.8 Hz); 13C NMR (75 MHz, CDCl3): δ 32.0, 33.8, 52.9, 53.0, 55.5, 114.8, 114.9, 115.1,
115.3, 116.8, 116.9, 132.3, 132.4, 133.4, 133.5, 158.8, 158.8; IR (ATR): 2953, 2849, 1596,
1572, 1474, 1415 cm−1; EIMS m/z (rel. int.): 310 [M]+ (10), 308 [M]+ (10), 230 (30), 229 (100),214 (30), 201 (10), 199 (20), 93 (30); HR-EIMS: [M]+ calcd for C10H14O4BrP 307.9813; found
307.9815.
Methyl 3-(4-formylphenoxy)-4-methoxybenzoate (8)
OMe

OMe
Br

HO

O

CuO, K 2CO 3

+
OHC

10

OHC

Pyridine, reflux
76%

CO2Me

CO2Me
8

9

 "Y0\º¿a4-I[TK\5"Y=E? (10) (4.50 g, 32.6 mmol)Íā*X%R(1.06 g, 7.67 mmol) āyĆ (II) (608 mg, 7.63 mmol) Î»GX3\ÈÂ (10 mL) 
3-E?[+2-4-S>+2¢ďāS:Y (9) (995 mg, 546 mmol) !x125 °C  16­ćxÐ×¿~ ædCelite®535RVS ÌüÌÂ!Ëé ¹
Ä!*WR,[P>-WH#] (Toluene) ãô 8 (1.18 g, 76%) !Compound 8: yellow solid; 1H NMR (300 MHz, CDCl3): δ 3.86 (3H, s), 3.89 (3H, s), 6.99 (2H,d, J=8.7 Hz), 7.06 (1H, d, J=8.4 Hz), 7.78 (1H, d, J=1.8 Hz), 7.83 (2H, d, J=8.7 Hz), 7.97 (1H,
dd, J=1.8, 8.4 Hz), 9.91 (1H, s); 13C NMR (75 MHz, CDCl3): δ 52.1, 56.1, 112.1, 116.3, 123.4,
123.8, 128.5, 131.2, 131.9, 142.6, 155.5, 163.0, 166.0, 190.7; IR (ATR): 1716, 1692, 1600,
1579, 1504, 1437 cm−1; EIMS m/z (rel. int.): 286 [M]+ (100), 255 (94), 127 (20); HR-EIMS:[M]+ calcd for C16H14O5 286.0841; found 286.0850; mp: 94.5−96.2 °C.
(E)-Methyl 3-(4-(2-bromo-5-methoxystyryl)phenoxy)-4-methoxybenzoate (14)
OMe
OMe

Br

O
+

OHC
CO2Me

O
O
P(OMe) 2

OMe

NaH

Br
CO2Me

THF, 0 °C
98%
OMe

8

7

14

 "Y0\º¿a7 (8.80 g, 28.6 mmol) Î» THF ÈÂ (4 mL) ! 0 °C t{60% »åy@>X%R (1.53 g, 38.2 mmol) !x 1 ­ć¨¤· 8 (6.64 g,
19.0 mmol) Î» THF ÈÂ (1 mL) !xÅ 24 ­ć¨¤Ďy"\T
51

A%R»ÈÂ!x~»¾À

!n¸»! EtOAc £u®¶!»Ďč®¶!Þā@>X%RcÑËé

¹Ä!

*WR,[P>-WH#] (Hexane:EtOAc = 10:1) ãô 14 (8.70 g, 98%) !Compound 14: colorless solid; 1H NMR (300 MHz, CDCl3): δ 3.80 (3H, s), 3.84 (3H, s), 3.86
(3H, s), 6.66 (1H, dd, J=2.7, 8.8 Hz), 6.93 (2H, d, J=8.8 Hz), 6.96 (1H, d, J=16.2 Hz), 7.00 (1H,d, J=8.5 Hz), 7.14 (1H, d, J=2.7 Hz), 7.30 (1H, d, J=16.2 Hz), 7.42 (1H, d, J=8.8 Hz), 7.48 (2H,d, J=8.8 Hz), 7.68 (1H, d, J=2.1 Hz), 7.86 (1H, dd, J=2.1, 8.5 Hz); 13C NMR (75 MHz, CDCl3):
δ 51.9, 55.4, 56.0, 111.5, 111.8, 114.7, 114.8, 117.3, 122.1, 123.0, 126.3, 127.2, 128.1, 130.6,
131.7, 133.4, 137.7, 144.3, 155.2, 157.4, 158.9, 166.1; IR (ATR): 2951, 2839, 1712, 1604, 1583,
1566, 1503, 1462, 1436, 1419 cm−1; CIMS m/z (rel. int.): 471 [M+H]+ (100), 470 [M]+ (90),469 [M+H]+ (100), 468 [M]+ (60), 390 (20); HR-CIMS: [M+H]+ calcd for C24H22O5Br
469.0651; found 69.0637; mp: 93.5−94.5 °C.
(E)-(3-(4-(2-Bromo-5-methoxystyryl)phenoxy)-4-methoxyphenyl)methanol (15)
OMe

OMe

O

O
LiAlH 4

Br
CO2Me

Br

THF, 0 °C
98%

OMe

HO
OMe
15

14

"Y0\º¿a14 (1.40 g, 2.9 mmol) Î» THF ÈÂ (10 mL) ! 0 °C t{»åyX:%R"YQA%R (0.20 g, 5.52 mmol) !xÅ 30 vć¨¤ÿÝā@>X%R*X%R»Ò»ÈÂ!x~!»Ďč»¾À!n¸»! EtOAc £u®¶®¶!Þā@>X%RcÑËé

¹Ä!*WR,[P>-WH#] (Hexane:EtOAc = 2:3) ãô 15(1.25 g, 98%) !Compound 15: colorless solid; 1H NMR (300 MHz, CDCl3): δ 3.77 (3H, s), 3.78 (3H, s), 4.54
(2H, s), 6.63 (1H, dd, J=3.0, 8.8 Hz), 6.88 (2H, d, J=8.6 Hz), 6.91 (1H, d, J=16.1 Hz), 6.93 (1H,d, J=8.6 Hz), 6.96 (1H, d, J=1.9 Hz), 7.08 (1H, dd, J=1.9, 8.6 Hz), 7.10 (1H, d, J=3.0 Hz), 7.24
(1H, d, J=16.1 Hz), 7.39 (1H, d, J=8.8 Hz), 7.42 (2H, d, J=8.6 Hz,); 13C NMR (75 MHz,CDCl3): δ 55.5, 56.1, 64.7, 111.6, 112.8, 114.8, 117.4, 120.0, 123.7, 126.2, 128.2, 130.8, 131.5,
133.5, 134.0, 137.9, 144.8, 150.9, 157.9, 159.0; IR (ATR): 3377, 2934, 1505, 1463, 1440, 1425
cm−1; CIMS m/z (rel. int.): 441 [M+H]+ (70), 440 [M]+ (60), 439 (70), 361 (100), 360 (60), 225(20); HR-CIMS: [M+H]+ calcd for C23H22O4Br 441.0701; found 441.0721; mp: 82.8−83.2 °C.

52

(E)-Dimethyl-3-(4-(2-bromo-5-methoxystyryl)phenoxy)-4-methoxybenzylphosphonate (17)
OMe

OMe

OMe

O

O

O
SOBr2

Br
HO

P(OMe) 3

Br

Benzene
0 °C − r.t.

OMe

Br

reflux98%(over 2 steps)

OMe
15

Br
(MeO) 2 P
O
OMe
17

16

 "Y0\º¿a15 (4.31 g, 9.85 mmol)  CH2Cl2 ÈÂ (3 mL) ! 0 °C t{ìy:)AY (1.00 mL, 12.8 mmol) !x2.5 ­ć¨¤»!x~!n¸

»! CH2Cl2 £u®¶!»Ďč»¾ÀÞā@>X%RcÑ

¹ÄfX\ā>XS:Y (5.85 mL, 49.5 mmol) !x 100 °C  24 ­ćxÐý¿~ædtoluene r¼

¹Ä!*WR,[P>-WH#] (Hexane:EtOAc = 15:85 ) ãô17 (5.12 mg, 98%) !Compound 17: yellow oil; 1H NMR (300 MHz, CDCl3): δ 3.07 (2H, d, J=21.3 Hz), 3.65 (3H,s), 3.69 (3H, s), 3.82 (6H, s), 6.68 (1H, dd, J=2.9, 8.8 Hz), 6.93 (2H, d, J=8.7 Hz,), 6.95 (1H, d,
J=2.5 Hz), 6.97 (1H, d, J=8.3 Hz), 6.98 (1H, d, J=16.4 Hz), 7.09 (1H, dd, J=2.5, 8.3 Hz), 7.16
(1H, d, J=2.9 Hz), 7.30 (1H, d, J=16.4 Hz), 7.44 (1H, d, J=8.8 Hz), 7.48 (2H, d, J=8.7 Hz); 13C
NMR (75 MHz, CDCl3): δ 31.2, 32.6, 52.9, 52.9, 55.2, 55.5, 56.0, 111.6, 113.0, 114.8, 116.8,
117.3, 122.5, 122.6, 123.9, 126.2, 127.7, 128.1, 130.3, 130.8, 131.5, 133.5, 137.9, 144.5, 150.5,
157.9, 159.0; IR (ATR): 2952, 2838, 1584, 1503, 1463, 1442, 1425 cm−1; EIMS m/z (rel. int.):
535[M]+ (100), 533 [M]+ (70), 455 (50), 454 (50), 343 (50), 208 (20), 165 (20), 44 (40);
HR-EIMS: [M]+ calcd for C25H27O6BrP 533.0697; found 533.0713.
1-Benzyloxy-4-((E)-3-(4-((E)-2-bromo-5-methoxystyryl)phenoxy)-4-methoxystyryl)-2-methox
ymethoxybenzene (18)
OMe
OMe

O

CHO

O
+

Br
(MeO) 2 P

NaH
OMOM
OBn

O
OMe

THF
0 °C, 94%

Br

OMe

MOMO
OBn

17

18

6

 "Y0\º¿a17 (5.44 g, 8.95 mmol) Î» THF (90 mL) ÈÂ! 0 °C t{60% »åy@>X%R (716 mg, 17.9 mmol) !x 1 ­ć¨¤· 6 (2.92 g,
10.7 mmol) Î» THF (10 mL) ÈÂ!xÅ 24 ­ć¨¤Ďy"\
TA%R»ÈÂ!x~ !n¸»! EtOAc £u®¶!»Ďč»¾À ®¶!Þā@>X%RcÑ Ëé ¹Ä53

!*WR,[P>-WH#] (Hexane:EtOAc = 4:1) ãô 18 (5.70 g, 94%) !

Compound 18: pale yellow oil; 1H NMR (400 MHz, CDCl3): δ 3.54 (3H, s), 3.84 (3H, s), 3.86
(3H, s), 5.16 (2H, s), 5.26 (2H, s), 6.70 (1H, dd, J=3.0, 8.8 Hz), 6.85−6.88 (2H, m), 6.97−7.03(5H, m), 7.17−7.19 (2H, m), 7.24−7.52 (12H, m); 13C NMR (100 MHz, CDCl3): δ 55.5, 56.1,
56.3, 71.0, 95.7, 111.6, 112.8, 114.5, 114.8, 117.3, 118.7, 121.1, 123.4, 126.1, 126.2, 127.1,
127.2, 127.9, 128.2, 128.6, 130.8, 131.1, 131.2, 131.4, 133.5, 137.0, 138.0, 144.8, 147.2, 148.7,
150.9, 158.0, 159.0; IR (ATR): 2931, 1588, 1503, 1462 cm−1; FABMS m/z (rel. int.): 680 [M]+(20), 678 [M]+ (20), 345 (20), 154 (50), 136 (50), 91 (100), 41 (100); HR-FABMS: [M]+ calcd
for C39H35BrO6 678.1617; found 678.1601.
1-Benzyloxy-4-(3-(4-(2-bromo-5-methoxyphenethyl)phenoxy)-4-methoxyphenethyl)-2-methox
ymethoxybenzene (19)OMe
TsNHNH2NaHCO 3Br

OMe

EtOC 2H 4OH
135 °C
97%

OMe

MOMO

OMe

MOMO

OMe

HO

H

20

OMe

MOMO

OH

19

O

Br

OBn

OMe

O

H

OBn

OMe

O

O

Br

18

OMe

OMe

O

MOMO

OH

21

OH
22

 18ē5.13 g, 7.55 mmolĔ EtOC2H4OH ÈÂ (75 mL) TsNHNH2 (14.0 g, 75.5 mmol)
Íā»å@>X%R (6.34 g, 75.5 mmol) !x135 °C  3 ­ćxÐ×¿~ædCelite®535RVS Ìü»!x EtOAc £u®¶!»Ďč»¾À ®¶!Þā@>X%RcÑ Ëé ¹Ä!
*WR,[P>-WH#] (Hexane:EtOAc = 9:1) ãô 19 (5.00 g, 97%) !Compound 19: colorless oil; 1H NMR (400 MHz, CDCl3): δ 2.77 (4H, br s), 2.85−2.97 (4H, m),
3.50 (3H, s), 3.74 (3H, s), 3.82 (3H, s), 5.11 (2H, s), 5,18 (2H, s), 6.63 (1H, dd, J=3.5, 8.8 Hz),6.68 (1H, d, J=2.0, 8.0 Hz), 6.69 (1H, d, J=3.2 Hz), 6.75 (1H, d, J=1.3 Hz), 6.80 (1H, d, J=8.2
Hz), 6.85 (2H, d, J=8.5 Hz), 6.88−6.91 (3H, m), 7.13 (2H, d, J=8.5 Hz), 7.29−7.43 (6H, m); 13C
NMR (100 MHz, CDCl3): δ 35.4, 37.0, 37.3, 38.7, 55.4, 56.1, 56.2, 71.1, 95.7, 112.6, 113.3,
114.5, 114.8, 116.1, 117.3, 117.8, 120.8, 122.3, 124.2, 127.2, 127.8, 128.5, 129.5, 133.2, 134.7,
135.0, 135.4, 137.3, 141.9, 145.0, 146.8, 147.3, 149.4, 156.1, 158.8; IR (ATR): 2928, 1589,
1504, 1469, 1423 cm−1; FABMS m/z (rel. int.): 707 [M+Na]+ (10), 705 [M+Na]+ (10), 684 [M]+(100), 682 [M]+ (10), 154 (70), 136 (60), 91 (100); HR-FABMS: [M]+ calcd for C39H39BrO6
682.1930; found 682.1903.
Compound 20: colorless oil; 1H NMR (300 MHz, CDCl3): δ 2.72−2.76 (4H, m), 2.89 (4H, br s),
3.78 (3H, s), 3.82 (3H, s), 5.09 (1H, br s), 5.18 (1H, br s), 6.53 (1H, dd, J=2.0, 8.0 Hz), 6.61
(1H, d, J=2.0 Hz), 6.69−6.78 (5H, m), 6.81 (2H, d, J= 8.6 Hz), 6.88 (1H, d, J=2.0 Hz), 6.88 (1H,d, J=2.0 Hz), 7.08 (2H, d, J=8.6 Hz), 7.20 (1H, t, J=8.0 Hz); 13C NMR (75 MHz, CDCl3): δ54

36.9, 37.0, 37.2, 38.0, 55.2, 56.1, 111.2, 112.6, 114.3, 115.2, 115.6, 117.3, 120.8, 120.9, 121.0,
124.1, 129.3, 129.4, 129.4, 134.7, 135.8, 141.5, 143.3, 143.4, 145.0, 149.3, 155.9, 159.4; IR(ATR): 3416, 2926, 2855, 1604, 1505, 1441 cm−1; EIMS m/z (rel. int.): 470 [M]+ (77), 349(100), 211 (41); HR-EIMS: [M]+ calcd for C30H30O5 470.2093; found 470.2093.
Compound 22: colorless oil; 1H NMR (500 MHz, CDCl3): δ 2.76 (4H, s), 2.88 (4H, s), 3.47 (3H,s), 3.77 (3H, s), 3.81 (3H, s), 5.21 (2H, s), 5.84 (1H, s), 6.68 (1H, dd, J=2.0, 8.0 Hz), 6.72−6.75(3H. m), 6.77 (1H, br d, J=7.5 Hz), 6.81 (2H, br s), 6.82 (2H, d, J=8.6 Hz), 6.88 (1H, d, J=2.0
Hz), 6.88 (1H, d, J=2.0 Hz), 7.09 (2H, d, J=8.6 Hz), 7.19 (1H, t, J=7.5 Hz); 13C NMR (125MHz, CDCl3): δ 37.0, 37.1, 37.4, 38.0, 55.1, 56.1, 56.3, 95.9, 111.1, 112.6, 114.2, 115.0, 115.7,
117.2, 120.8, 120.8, 122.9, 124.2, 129.2, 129.4, 133.6, 134.6, 135.7, 143.4, 144.2, 144.3, 145.0,
149.3, 155.9, 159.5; IR (ATR): 3439, 2931, 1603, 1583, 1504, 1454, 1439 cm−1; EIMS m/z (rel.
int.): 514 [M]+ (13), 482 (100), 361 (31), 359 (78), 347 (30), 211 (48), 45 (37); HR-EIMS: [M]+calcd for C32H34O6 514.2355; found 514.2362.
4-(3-(4-(2-Bromo-5-methoxyphenethyl)phenoxy)-4-methoxyphenethyl)-2-(methoxymethoxy)phenol (21)
OMe

OMe

O

O
Br

OMe

H 2, Pd(OH) 2
MeOH/CHCl 3 = 1:9
93%
MOMO

Br

OMe

MOMO
OH

OBn
19

21

 19 (45.3 mg, 66.3 µmol)  CHCl3MeOH = 9:1 ÈÂ (2.5 mL)  Pd(OH)2C (4.0 mg)!x»åê¦ 10 vćÊ ¨¤~ ædCelite®535RVS ÌüÌ
Â!Ëé ¹Ä!*WR,[P>-WH#] (CH2Cl2) ãô 21 (36.6
mg, 93%) !Compound 21: yellow oil; 1H NMR (400 MHz, CDCl3): δ 2.76 (4H, br s), 2.85−2.97 (4H, m),
3.49 (3H, s), 3.74 (3H, s), 3.82 (3H, s), 5.13 (2H, s), 5.78 (1H, s), 6.63 (1H, dd, J=3.2, 8.8 Hz),6.68 (1H, dd, J=2.0, 8.0 Hz), 6.70 (1H, d, J=5.6 Hz), 6.72 (1H, d, J=1.6 Hz), 6.82−6.84 (4H, m),
6.88−6.89 (2H, m), 7.13 (2H, d, J=8.4 Hz), 7.42 (1H, d, J=8.8 Hz); 13C NMR (100 MHz,CDCl3): δ 35.4, 37.2, 37.4, 38.7, 55.4, 56.1, 56.4, 96.0, 112.7, 113.3, 115.0, 115.8, 116.1, 117.3,
120.8, 123.0, 124.2, 129.5, 133.3, 133.6, 134.7, 135.4, 141.9, 144.2, 144.4, 145.0, 149.4, 158.8;
IR (ATR): 3447, 2931, 1604, 1505, 1471 cm−1; EIMS m/z (rel. int.): 594 [M]+ (71), 592 [M]+(69), 562 (76), 560 (74), 439 (95), 437 (92), 427 (84), 425 (96), 361 (96), 239 (46), 211 (100),135 (42), 90 (28), 45 (58); HR-EIMS: [M]+ calcd for C32H33BrO6 529.1461; found 592.1469.

554-(3-(4-(2-Bromo-5-methoxyphenethyl)phenoxy)-4-methoxyphenethyl)-2-(methoxymethoxy)phenyl trifluoromethanesulfonate (23)
OMe

OMe

O

O

Br

Tf2O, DMAPBr

CH2Cl2, 96%
OMe

OMe

MOMO

MOMO

OH

OTf

23

21

 21 (35.9 mg, 60.0 mmol)  CH2Cl2 ÈÂ (1 mL) !−78 °C t{DMAP (9.0 mg, 121µmol) >XHY)[S9\4YM\āÎ»Ò (12.9 µL, 121 µmol) !x1 ­ć¨¤Íā»å@>X%R»ÈÂ!x~ !n¸»! CH2Cl2 £u®¶!»Ďč»¾ÀÞā@>X%RcÑ Ëé ¹Ä!*
WR,[P>-WH#] (Hexane:EtOAc = 3:1) ãô 23 (42.2 mg, 96%) !Compound 23: colorless oil; 1H NMR (400 MHz, CDCl3): δ 2.80−2.95 (6H, m), 2.95−2.97 (2H,m), 3.49 (3H, s), 3.74 (3H, s), 3.83 (3H, s), 5.18 (2H, s), 6.64 (1H, dd, J=3.2, 8.8 Hz), 6.71 (1H,d, J=2.8 Hz), 6.73 (1H, d, J=1.6 Hz), 6.77 (1H, dd, J=2.4, 8.4 Hz), 6.84−6.87 (3H, m), 6.90 (1H,d, J=8.2), 7.00 (1H, d, J=1.6 Hz), 7.09 (1H, d, J=8.4 Hz,), 7.14 (2H, d, J= 8.8 Hz), 7.42 (1H, d,
J=8.4 Hz); 13C NMR (100 MHz, CDCl3): δ 35.4, 36.6, 37.7, 38.7, 55.4, 56.1, 56.5, 95.0, 112.7,
113.4, 114.8, 116.1, 116.6, 117.4, 120.6, 122.0, 122.1, 124.2, 129.5, 133.3, 133.9, 135.6, 137.3,
141.8, 143.3, 145.2, 148.8, 149.6, 156.0, 158.9; IR (ATR): 2924, 2851, 1604, 1504, 1470, 1420
cm−1; FABMS m/z (rel. int.): 726 [M]+ (20), 724 [M]+ (20), 525 (40), 45 (100); HR-FABMS:[M]+ calcd for C33H32BrF3O8S 724.0953; found 724.0969.
4-(4-methoxy-3-(4-(5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)phenoxy)phenethyl)-2-methoxymethoxyphenyl trifluoromethanesulfonate (24)
OMe

OMe

O

O
O

Br

OMe

B 2pin 2, Pd(PPh 3)4, K 3PO 4

MOMO

Dioxane, 100 °C
81%
OTf

23

B

O

OMe

MOMO

OTf

24

 "Y0\º¿a23 (12.0 mg, 166 µmol)<>W+4>XH&AYH(4H#\DW
3%R (2.0 mg, 1.66 µmol)F4(G@/W]>)3N[\ (8.4 mg, 332 µmol) X\ā_*X%R (10.5 mg, 500 µmol) Î»3)+1\ÈÂ (100 mL) ! 100 °C xÐ
12 ­ć¨¤~ ædCelite®535RVS ÌüÌÂ!Ëé ¹Ä!
*WR,[P>-WH#] (Hexane:EtOAc = 4:1) ãô 21 (10.0 mg, 81%) !Compound 24: colorless oil; 1H NMR (400 MHz, CDCl3): δ 1.35 (12H, s), 2.78−2.86 (4H, m),
3.11−3.15 (4H, m), 3.49 (3H, s), 3.80 (3H, s), 3.83 (3H, s), 5.18 (2H, s), 6.71 (1H, d, J=2.4 Hz),6.74 (1H, dd, J=2.4, 8.4 Hz), 6.76 (1H, d, J=2.0, Hz), 6.77 (1H, dd, J=2.0, 8.4 Hz), 68.5 (1H,
56

dd, J=2.1, 8.6 Hz), 6.86 (2H, d, J=8.6 Hz), 6.86 (1H, d, J=2.1 Hz), 6.90 (1H, d, J=8.4 Hz), 7.01
(1H, d, J=2.0 Hz,), 7.09 (1H, d, J=8.4 Hz), 7.21 (2H, d, J=8.4 Hz), 7.79 (1H, d, J=8.4 Hz); 13C
NMR (100 MHz, CDCl3): δ 24.9, 36.6, 37.7, 38.9, 39.0, 55.0, 56.1, 56.5, 83.2, 95.0, 110.6,
112.7, 115.1, 116.6, 117.2, 120.6, 121.1, 122.0, 124.1, 129.5, 133.9, 136.9, 137.3, 138.2, 143.3,
145.3, 148.8, 149.6, 151.4, 155.8, 161.8; IR (ATR): 2930, 1602, 1505, 1421 cm−1; FABMS m/z(rel. int.): 795 [M+Na]+ (10), 772 [M]+ (20), 615 (30), 525 (40), 359 (60), 45 (100);
HR-FABMS: [M]+ calcd for C39H44F3O10SB 772.2700; found 772.2712.
Dimethylmethoxymethylriccardin C (25)
OMe

OMe
O
O

B

O

OMe

Pd 2(dba) 3, SPhos
anhydrous Na 2CO 3

MOMO

24

OMe

O

DMF
(0.005 M)
72%

O
H

MeO
MOMO

OMe

MOMO

OTf

25

OTf

26

 "Y0\º¿a24 (79.2 mg, 103 µmol)  DMFÈÂ (100 mL) >X4(3K\3X=\"6>\)3DW3%R (9.4 mg, 10.3 µmol)SPhos (8.3 mg, 20.7 µmol) Íā*X%R (32.6 mg, 308 µmol) !x100 °CxÐ12­ć2]Y?:U]Is¨¤~ædCelite®535RVSÌüÌÂ!>Y'\r¼Ëé

¹Ä!*WR,[P>-WH#] (Hexane:EtOAc = 9:1) ãô25 (36.5 mg,72%) !
Compound 25: colorless oil; 1H NMR (500 MHz, CDCl3): δ 2.52−2.68 (3H, m), 2.82−2.88 (3H,m), 2.95−3.00 (1H, m), 3.09−3.14 (1H, m), 3.33 (3H, s), 3.89 (3H, s), 3.94 (3H, s), 4.93 (1H, d,
J=6.0 Hz), 5.00 (1H, d, J=6.0 Hz), 5.38 (1H, d, J=1.9 Hz), 6.25 (1H, dd, J=1.5, 7.5 Hz), 6.66
(1H, br s), 6.72 (1H, d, J=1.5 Hz), 6.72 (1H, br s), 6.77 (1H, br s), 6.78 (1H, dd, J=1.9, 8.0 Hz),6.82 (1H, br s), 6.83 (1H, d, J=7.5 Hz), 6.88 (1H, d, J=8.0 Hz), 6.91 (1H, br s), 6.96 (1H, d,
J=2.7 Hz), 7.04 (1H, d, J=8.3 Hz); 13C NMR (125 MHz, CDCl3): δ 35.7, 37.2, 37.9, 38.3, 55.2,
56.1, 56.2, 95.1, 111.4, 111.7, 115.2, 115.4, 116.6, 121.5, 122.3, 122.5, 123.5, 128.8, 129.0,
129.6, 131.1, 132.3, 132.5, 133.7, 139.6, 141.3, 143.2, 146.8, 148.5, 152.7, 153.8, 159.1; IR(ATR): 2931, 2841, 1605, 1505, 1442, 1420 cm−1; EIMS m/z (rel. int.): 497 [M+H]+ (51), 496[M]+ (100), 451 (66), 225 (51); HR-EIMS: [M]+ calcd for C32H32O5 496.2250; found 496.2250.
Compound 26: colorless oil; 1H NMR (300 MHz, CDCl3): δ 2.78−2.83 (4H, m), 2,87 (4H, br s),
3.47 (3H, s), 3.75 (3H, s), 3.79 (3H, s), 5.16 (2H, s), 6.70−6.87 (9H, m), 6.99 (1H, d, J=2.0 Hz),7.08 (1H, d, J=8.3 Hz), 7.09 (2H, d, J=8.6 Hz), 7.15−7.22 (1H, m); 13C NMR (75 MHz,CDCl3): δ 36.5, 36.9, 37.5, 38.0, 55.0, 55.9, 56.3, 94.9, 111.1, 112.6, 114.1, 116.5, 117.2, 120.6,
120.8, 121.9, 121.9, 123.5, 124.1, 129.2, 133.8, 135.8, 137.2, 143.2, 143.3, 145.1, 148.7, 149.5,
57155.8, 159.5; IR (ATR): 2934, 1604, 1584, 1504, 1419 cm−1; EIMS m/z (rel. int.): 646 [M]+(85), 525 (100), 347 (72), 211 (36); HR-EIMS: [M]+ calcd for C33H33F3O8S 646.1848; found646.1857.
Trimethylriccardin C (28)
OMe
O
OMe

OMe

O

O
O

B

O

OMe

Pd 2(dba) 3, SPhos
2M Na 2CO 3
DMF
48%
MeO

MeO

MeO
OMe

MeO
MeO

OTf

OMe

28

27

O
OMe
29

 "Y0\º¿a>X4(3K\3X=\"6>\)3DW3%R (4.0 mg, 4.30 µmol)
SPhos (3.6 mg, 8.70 µmol)  27 (32.8 mg, 44.0 µmol) !Î» DMF (8.8 mL) Èõ 2M Íā*X%R (67 ml, 0.13 mmol) !x100 °C xÐ12 ­ć2]Y?:U]Is¨¤~Ëé

ædCelite®535RVS Ìü!>Y'\r¼

¹Ä!X1$,Y HPLC (¿û 3.5min, l¥­ć 47 v) v28 (10.0 mg, 48%) ×yeăi 29 (5.1 mg, 25%) !Compound 28: colorless oil; 1H NMR (400 MHz, CDCl3): δ 2.63−2.86 (3H, br s), 2.89−2.97(4H, m), 3.06−2.97 (2H, m), 3.06−3.33 (1H, m), 3.67 (3H, s), 3.88 (3H, s), 3.94 (3H, s), 5.36
(1H, d, J=1.9 Hz), 6.24 (1H, dd, J=1.5, 7.6 Hz), 6.44 (1H, d, J=1.5 Hz), 6.73−6.83 (6H, m),
6.83 (1H, d, J=7.9 Hz), 6.89 (1H, d, J=8.3Hz), 6.96 (1H, d, J=2.8 Hz), 7.06 (1H, d, J=8.5 Hz);13

C NMR (100 MHz, CDCl3): δ 35.6, 37.3, 38.1, 38.2, 55.2, 55.2, 56.1, 111.1, 111.4, 111.7,

115.4, 116.6, 121.4, 121.7, 122.3, 127.5, 129.2, 129.6, 130.9, 132.4, 132.4, 133.7, 139.7, 141.2,
143.2, 146.8, 148.6, 152.7, 155.9, 159.1; IR (ATR): 2931, 2834, 1605, 1584, 1505, 1464, 1419
cm−1; EIMS m/z (rel. int.): 466 [M]+ (100), 239 (75); HR-EIMS: [M]+ calcd for C31H30O4
466.2144; found 466.2163.
Compound 29: colorless oil; 1H NMR (400 MHz, CDCl3): δ 2.62−2.79 (8H, m), 3.68 (6H, s),
3.79 (6H, s), 3.85 (6H, s), 6.70 (2H, br s), 6.71−6.83 (16H, m), 6.87 (2H, d, J=2.0 Hz), 6.89
(2H, d, J=2.5 Hz), 7.00 (2H, d, J=7.5 Hz), 7.10 (2H, d, J=8.4 Hz); 13C NMR (100 MHz,CDCl3): δ 36.5, 36.6, 37.5, 38.6, 55.2, 55.4, 56.1, 110.9, 111.0, 112.6, 114.4, 116.9, 120.3,
120.9, 124.4, 127.8, 129.2, 130.7, 131.3, 131.5, 134.8, 136.4, 142.0, 142.3, 145.0, 149.7, 156.0,
156.7, 158.9; IR (ATR): 3006, 2926, 2854, 1604, 1576, 1503, 1463, 1419 cm−1; FABMS m/z:
933 [M+H]+ (2); HR-FABMS: [M+H]+ calcd for C62H61O8 933.4366; found 933.4347.
58

Dimethylriccardin C (4)
OMe

OMe

O

O
Dowex ® 50WX2−100
MeOH/EtOAc = 2:1
70 °C
83%

MeO
MOMO

MeO
HO
4

25

 25 (39.0 mg, 81.6 mol)  MeOHEtOAc = 2:1 ÈÂ (1 mL)  Dowex® 50WX2−100 !
x70 °C xÐ3 ­ć¨¤~ ædCelite®535RVS ÌüÌÂ!Ë
é ¹Ä!*WR,[P>-WH#] (HexaneCH2Cl2 = 1:1) ãô
4 (32.4 mg, 83%) !Compound 4: colorless oil; 1H NMR (400 MHz, CDCl3): δ 2.64−2.75 (5H, m), 2.86−2.99 (2H,m), 3.05−3.11 (1H, m), 3.90 (3H, s), 3.94 (3H, s), 4.80 (1H, s), 5.42 (1H, d, J=2.0 Hz), 6.28
(1H, dd, J=1.6, 7.6 Hz), 6.43 (1H, d, J=1.6 Hz), 6.42−6.82 (6H, m), 6.88 (2H, dd, J=1.6, 8.4
Hz), 7.02 (1H, d, J=2.8 Hz), 7.10 (1H, d, J=8.4 Hz); 13C NMR (125 MHz, CDCl3): δ 35.1, 37.1,
37.7, 38.2, 55.4, 56.1, 111.7, 112.6, 115.9, 116.3, 116.6, 121.4, 121.6, 122.5, 122.7, 124.5,
128.0, 129.0, 129.3, 131.5, 132.6, 133.8, 139.3, 142.0, 143.6, 146.8, 148.6, 151.9, 152.9, 159.9;
IR (ATR): 3463, 2929, 2854, 1605, 1504, 1442, 1420 cm−1; EIMS m/z (rel. int.): 452 [M]+(100), 225 (68); HR-EIMS: [M]+ calcd for C30H28O4 452.1988; found 452.1990.
Dimethyl asterelin A (30)
OMe

OMe

O

OMe

O

O

VOCl3
CH2Cl2, 0 °C
58%

MeO

Cl
MeO

HO

MeO
O

4

30

O
31

 "Y0\º¿a4 (3.0 mg, 6.64 µmol) Î» CH2Cl2 (3 mL) ÈÂ! 0 °C t{VOCl3 (2.00 µL, 19.9 µmol) !x 20 vć¨¤fÞā@>X%R»ÈÂ!x~ !n¸»! CH2Cl2 £u®¶!»Ďč»¾À ®
¶!Þā@>X%RcÑ Ëé ¹Ä!*WR,[P>-WH#] (Hexane:EtOAc = 2:1) ãô 30 (2.8 mg, 58%)  31 (0.8 mg, 27%) !Compound 30: colorless oil; 1H NMR (300 MHz, CDCl3): δ 2.61–2.82 (3H, m), 2.96–3.03 (1H,m), 3.08–3.14 (1H, m), 3.12–3.20 (2H, m), 3.38–3.43 (1H, m), 3.87 (3H, s), 3.93 (3H, s), 5.41
(1H, br s), 5.92 (1H, dd, J=2.5, 8.2 Hz,), 6.30 (1H, dd, J=2.5, 8.2 Hz), 6.33 (1H, dd, J=1.4, 8.0
Hz), 6.66 (1H, dd, J=2.7, 8.2 Hz), 6.82 (1H, d, J=2.2 Hz), 6.84 (2H, d, J=1.4 Hz), 6.93 (1H, d,59

J=2.2 Hz), 7.05 (1H, d, J=8.0 Hz), 7.20 (1H, d, J=2.0 Hz), 7.29 (1H, dd, J=2.7, 8.2 Hz); 13C
NMR (100 MHz, CDCl3): δ 34.8, 37.4, 37.6, 38.8, 55.7, 56.1, 94.1, 110.2, 111.5, 111.9, 119.9,
120.6, 120.8, 121.4, 122.0, 123.8, 123.9, 130.3, 130.6, 133.8, 135.2, 137.5, 138.5, 147.3, 149.3,
156.1, 156.4, 157.0, 159.6; IR (ATR): 2925, 2855, 1731, 1609, 1503, 1436 cm−1; EIMS m/z (rel.
int.): 450 [M]+ (100), 225 (42), 211 (54), 44 (67); HR-EIMS: [M]+ calcd for C30H26O4 450.1831;
found 450.1829.
Compound 31: colorless oil; 1H NMR (500 MHz, CDCl3): δ 2.69–2.75 (2H, m), 2.88–2.92 (1H,m), 3.06–3.10 (1H, m), 3.18–3.24 (2H, m), 3.29–3.38 (2H, m), 3.88 (3H, s), 3.93 (3H, s), 5.48
(1H, d, J=2.0 Hz), 5.96 (1H, dd, J=2.7, 8.3 Hz), 6.37 (1H, dd, J=2.7, 8.3 Hz), 6.74 (1H, dd,
J=2.7, 8.3 Hz), 6.82 (1H, d, J=2.2 Hz), 6.84 (1H, d, J=8.3 Hz), 6.91 (1H, d, J=2.2 Hz), 6.92
(1H, dd, J=2.2, 8.3 Hz), 7.16 (1H, s), 7.23 (1H, s), 7.35 (1H, dd, J=2.7, 8.3 Hz); 13C NMR (125MHz, CDCl3): δ 29.7, 34.0, 34.7, 37.2, 38.6, 55.7, 56.1, 94,1, 111.7, 111.9, 112.0, 116.7, 119.7,
120.3, 121.4, 121.7, 123.2, 124.6, 128.0, 130.2, 130.8, 133.1, 134.7, 135.4, 137.8, 147.2, 149.8,
154.7, 156.7, 157.5, 160.2; IR (ATR): 2929, 2858, 2841, 1608, 1504, 1464, 1426 cm−1; EIMS
m/z (rel. int.): 484 [M]+ (100), 343 (15), 242 (39), 211 (66), 44 (79); HR-EIMS: [M]+ calcd for
C30H25O4Cl 484.1441; found 481.1438.
Asterelin A (1)
OMe

OH

O

O
BBr 3
CH2Cl2, 0 °C
76%

MeO

HO

O

O
Asterelin A (1)30

 "Y0\º¿a30 (2.10 mg, 4.66 mmol) ! CH2Cl2 (1 mL) Èõ 0 °C t{
_ìyM%å (23.3 µL, 23.3 µmol, 1M in CH2Cl2) !x 2 ­ć¨¤»!x~!n¸CH2Cl2  3 £u

@>X%RcÑËé®¶!Ďč»¾ÀÞā

¹Ä!*WR,[P>-WH#](Hexane:EtOAc = 2:1) ãô Asterelin A (1) (1.50 mg, 76%) !Asterelin A (1): colorless oil; 1H NMR (500 MHz, acetone-d6): δ 2.57 (1H, ddd, J=3.5, 12.5,
12.5 Hz), 2.71 (1H, dd, J=3.5, 13.0 Hz), 2.76 (1H, dd, J=3.5, 12.0 Hz), 2.97 (1H, ddd, J=3.5,
5.5, 13.5 Hz), 3.12 (1H, ddd, J=3.5, 5.5, 13.0 Hz), 3.22 (1H, ddd, J=3.5, 5.5, 13.0 Hz), 3.33 (1H,
ddd, J=3.5, 3.5, 13.0 Hz), 3.45 (1H, ddd, J=3.0, 13.0, 13.0 Hz), 5.33 (1H, s), 5.98 (1H, dd,
J=2.2, 8.0 Hz), 6.28−6.30 (2H, m), 6.61 (1H, dd, J=3.0, 8.5 Hz), 6.83 (2H, br d, J=8.6 Hz), 6.84
(1H, d, J=2.0 Hz), 6.87 (1H, d, J=2.0 Hz), 7.14 (1H, d, J=8.0 Hz), 7.25 (1H, br s), 7.47 (1H, dd,
J=2.0, 8.5 Hz); 13C NMR (125 MHz, acetone-d6): δ 35.8, 38.7, 39.1, 40.0, 97.5, 111.4, 113.7,
117.3, 118.0, 120.6, 122.1, 122.2, 122.9, 123.6, 125.4, 126.1, 131.4, 132.6, 133.9, 137.0, 139.2,
140.0, 147.0, 148.4, 157.8, 158.0, 158.6, 159.0; IR (ATR): 3378, 2925, 1691, 1608, 1503, 1437
60

cm−1; EIMS m/z (rel. int.): 422 [M]+ (100), 211 (95); HR-EIMS: [M]+ calcd for C28H22O4
422.1518; found 422.1531.
10’-Bromo-dimethylriccardin C (38)
OMe

OMe

O

O
NBS

Br

MeCN
81%

MeO

MeO
HO

HO
4

38

 "Y0\º¿a4 (4.2 mg, 9.28 µmol) Î» MeCN (200 µL) ÈÂ N-I[T4,2$Q? (1.82 mg, 10.2 µmol) !xÅ 25 vć¨¤~ ædËé ¹Ä!*WR,[P>-WH#] (Hexane:Et2O = 1:1) ãô 38 (4.0 mg,81%) !
Compound 38: colorless oil; 1H NMR (500 MHz, CDCl3): δ 2.52−2.57 (1H, m), 2.71−3.01 (6H,m), 3.03−3.13 (1H, m), 3.91 (3H, s), 3.95 (3H, s), 4.88 (1H, s), 5.41 (1H, d, J=2.0 Hz), 6.34
(1H, s), 6.78−6.83 (3H, m), 6.86−6.90 (4H, m), 7.05 (1H, d, J=2.7 Hz), 7.10 (1H, d, J=8.5 Hz),7.14 (1H, s); 13C NMR (125 MHz, CDCl3): δ 34.9, 35.6, 37.6, 38.2, 55.4, 56.1, 111.8, 112.6,
114.4, 116.0, 116.8, 118.7, 121.6, 122.5, 122.9, 126.4, 126.7, 129.0, 129.3, 132.0, 133.4, 134.9,
139.2, 140.5, 143.8, 146.9, 148.9, 151.3, 153.0, 160.1; IR (ATR): 3448, 2930, 1605, 1505 cm−1;
EIMS m/z (rel. int.): 532 [M]+ (100), 530 [M]+ (100), 227 (40); HR-EIMS: [M]+ calcd for
C30H27BrO4 530.1093; found 530.1099.
10’-Iodo-dimethylriccardin C (40)
OMe

OMe

O

O
NaI, NaOCl, NaOH
MeOH
75%

MeO

I
MeO

HO

HO

4

40

"Y0\º¿a4 (13.4 mg, 29.6 µmol)V%y@>X%R (4.5 mg, 30.0 µmol)»āy
@>X%R (4.6 mg, 32.9 µmol) Î» MeOH (1 mL) ÈÂ NaOCl (6.2 µL, 88.8 µmol)!xÅ 3 ­ć¨¤fÞā@>X%R»ÈÂ~ !n¸2 N HCl !x»! CH2Cl2 £u®¶!»Ďč»¾À ¹Ä!*WR,[P>-WH#] (Toluene) ãô 40 (12.9 mg, 75%) !Compound 40: colorless oil; 1H NMR (500 MHz, CDCl3): δ 2.67−2.71 (2H, m), 2.75−2.82 (2H,m), 2.88−2.97 (2H,m), 2.98−3.03 (2H, m), 2.90−3.03 (4H, m), 3.90 (3H, s), 3.95 (3H, s), 4.87
(1H, s), 5.36 (1H, d, J=2.1 Hz), 6.37 (1H, s), 6.79−6.91 (7H, m), 7.03 (1H, d, J=2.5 Hz), 7.09
61

(1H, d, J=9.0 Hz), 7.40 (1H, s); 13C NMR (125 MHz, CDCl3): δ 35.0, 36.1, 38.2, 41.7, 55.4,
56.1, 89.3, 111.9, 112.7, 116.1, 116.1, 117.9, 121.7, 122.6, 122.9, 126.3, 127.3, 129.0, 129.3,
132.1, 133.1, 139.2, 141.5, 143.7, 143.9, 147.0, 149.0, 152.3, 153.0, 160.2; IR (ATR): 3458,
2947, 2352, 1605, 1506, 1420 cm−1; EIMS m/z (rel. int.): 578 [M]+ (100), 452 (30), 225 (30);
HR-EIMS: [M]+ calcd for C30H27O4I 578.0954; found 578.0958.
10’-Iodo-dimethylacetylriccardin C (41)
OMe

OMe

O

O
I

Ac2O, DMAPI

THF, 97%

MeO

MeO

HO

AcO

40

41

 "Y0\º¿a40 (7.0 mg, 12.1 µmol)  N,N-3S:Y-4-"QBGX3\ (1.5 mg,
12.2 µmol) Î»THF (1 mL) ÈÂÎ»Āā (2.0 µL, 21.2 µmol) !xÅ2­ć¨¤ĎÍā»å@>X%R»ÈÂ!x~®¶!»Ďč»¾À!n¸»!EtOAc£u

¹Ä!*WR,[P>-WH#](Hexane:EtOAc = 4:1) ãô41 (7.3 mg, 97%) !Compound 41: colorless oil; 1H NMR (400 MHz, CDCl3): δ 2.03 (3H, s), 2.64 (1H, dd, J=10.6,
10.6 Hz), 2.76−3.00 (7H, m), 3.88 (3H, s), 3.95 (3H, s), 5.27 (1H, d, J=2.0 Hz), 6.56 (1H, s),
6.76−6.82 (4H, m), 6.86 (1H, dd, J=2.8, 8.4 Hz), 6.89−6.93 (2H, m), 6.95 (1H, d, J=2.8 Hz),6.97 (1H, d, J=8.8 Hz), 7.58 (1H, s); 13C NMR (100 MHz, CDCl3): δ 20.8, 35.3, 36.5, 38.2,
41.5, 55.3, 56.1, 97.6, 111.7, 112.0, 115.7, 115.7, 121.8, 122.5, 122.7, 124.2, 127.8, 129.4,
129.5, 132.0, 132.8, 133.8, 139.5, 142.6, 143.0, 143.9, 147.0, 147.7, 149.1, 152.7, 159.8, 169.1;
IR (ATR): 2933, 1763, 1606, 1506, 1470 cm−1; EIMS m/z (rel. int.): 620 [M]+ (100), 578 (44);
HR-EIMS: [M]+ calcd for C32H29O5I 620.1060; found 620.1067.
Dimethylacetylcavicularin (42)
OMe

I
MeO
AcO

OMe

MeO
O

O

O

Pd(OAc) 2, n-Bu 3P
Ag2CO 3
DMF
50%

MeO
OAc

MeO

42

41

AcO

43

 "Y0\º¿a41 (4.0 mg, 6.45 µmol) Î» DMF ÈÂ (1 mL) Íāą (1.8 mg,
7.09 µmol)ĀāDW3%R (0.3 mg, 1.34 µmol)>X-n-I:YH(4H#\ (0.3 µL,
14.5 µmol) !x120 °C xÐ6 ­ć¨¤~ ædCelite®535RVS 
62ÌüÌÂ!Ëé ¹Ä!*WR,[P>-WH#] (HexaneEt2O = 3:1)
ãô 42 (1.6 mg, 50%)  43 (1.0 mg, 31%) !Compound 42: colorless oil; 1H NMR (500 MHz, CDCl3): δ 2.30 (1H, ddd, J=3.0, 14.0, 14.0Hz), 2.52 (1H, ddd, J=3.0, 12.0, 12.0 Hz), 2.64−2.78 (4H, m), 2.86−2.93 (2H, m), 3.87 (3H, s),
3.94 (3H, s), 6.01 (1H, dd, J=2.5, 8.5 Hz), 6.08 (1H, dd, J=2.0, 8.5 Hz), 6.40 (1H, dd, J=2.0, 8.5
Hz), 6.66 (1H, s), 6.73 (1H, dd, J=2.5, 8.5 Hz), 6.74 (1H, dd, J=2.5, 8.5 Hz), 6.79 (1H, d, J=8.5
Hz), 6.84 (1H, d, J=2.5 Hz), 6.85 (1H, s), 6.94 (1H, d, J=8.0 Hz), 7.04 (1H, d, J=8.0 Hz); 13C
NMR (125 MHz, CDCl3): δ 20.7, 29.7, 30.1, 30.3, 37.6, 38.1, 55.2, 56.7, 111.2, 111.5, 114.2,
115.4, 117.9, 119.8, 122.3, 123.8, 127.3, 129.4, 130.1, 130.3, 130.5, 130.7, 132.1, 133.1, 134.3,
139.3, 141.1, 145.6, 151.6, 154.4, 158.8, 168.8; IR (ATR): 2925, 2852, 1749, 1606, 1505, 1457,
1438 cm−1; EIMS m/z (rel. int.): 492 [M]+ (40), 450 (100), 359 (30); HR-EIMS: [M]+ calcd for
C32H28O5 492.1937; found 492.1931.
Compound 43: colorless oil; 1H NMR (500 MHz, CDCl3): δ 2.01 (3H, s), 2.57−2.69 (3H, m),
2.71−2.79 (1H, m), 2.80−2.89 (3H, m), 2.97−3.08 (2H, m), 3.88 (3H, s), 3.95 (3H, s), 5.33 (1H,d, J=2.0 Hz), 6.51 (1H, dd, J=2.0, 8.0 Hz), 6.62 (1H, d, J=2.0 Hz), 6.67 (1H, br d, J=8.0 Hz),6.74 (1H, br d, J=7.5 Hz), 6.78 (1H, dd, J=2.0, 8.5 Hz), 6.80 (1H, d, J=2.5 Hz), 6.80 (1H, dd,
J=2.5, 8.5 Hz), 6.89 (1H, d, J=8.5 Hz), 6.94 (1H, d, J=7.5 Hz), 6.92 (1H, br s), 6.95 (1H, d,
J=2.0 Hz), 6.99 (1H, d, J=8.5 Hz); 13C NMR (125 MHz, CDCl3): δ 20.8, 35.3, 37.2, 37.6, 38.2,
55.2, 56.1, 111.5, 111.8, 115.5, 116.5, 121.5, 122.3, 122.5, 122.8, 127.5, 129.2, 129.5, 129.7,
131.5, 132.2, 132.4, 133.4, 139.5, 141.3, 142.4, 146.9, 147.4, 148.5, 152.8, 159.4, 169.3; IR(ATR): 2926, 2855, 1761, 1606, 1505, 1420 cm−1; EIMS m/z (rel. int.): 494 [M]+ (92), 452(100), 225 (60); HR-EIMS: [M]+ calcd for C32H30O5 494.2193; found 494.2106.
Cavicularin (2)
MeO
O

MeO
O

OAc

MeO

42

HO
O

K 2CO 3

BBr 3

MeOH, r.t.

CH2Cl271%
over 2 steps

OH

MeO

32

HO

OH

(±)-Cavicularin (2) 42 (1.2 mg, 2.44 µmol) S9B]YÈÂ (1 mL) Íā*X%R (1.0 mg, 7.24 µmol)!xÅ5­ć¨¤2 N HCl !x~ !n¸»!EtOAc£u ®¶!Ďč»¾ÀÞā@>X%RcÑ Ëé
¹Ä!*WR,[P>-WH#] (Hexane:EtOAc = 4:1) ãô 32 (1.1 mg,
100%) !
 32 (1.8 mg, 4.00 µmol) Î»CH2Cl2 ÈÂ (1 mL) _ìyM%å (10.2 µL, 10.2µmol, 1M in CH2Cl2) !x0 °Ct{24­ć¨¤»!x~ !n¸»!CH2Cl2£u ®¶!Ďč»¾ÀÞā@>X%Rc63Ñ Ëé ¹Ä!*WR,[P>-WH#] (Hexane:EtOAc = 7:3)
ãô cavicularin (2) (1.2 mg, 71%) !Cavicularin (2): colorless oil; 1H NMR (500 MHz, CDCl3): δ 2.28 (1H, ddd, J=3.5, 12.5, 14.0Hz), 2.55 (1H, ddd, J=3.5, 12.5, 14.0 Hz), 2.63−2.78 (4H, m), 2.92−2.98 (2H, m), 4.75 (1H, s),
4.85 (1H, s), 6.10 (1H, dd, J=2.5, 8.5 Hz), 6.11 (1H, d, J=2.5 Hz), 6.15 (1H, dd, J=2.5, 8.5 Hz),6.40 (1H, s), 6.47 (1H, dd, J=2.5, 8.5 Hz), 6.68 (1H, s), 6.72 (1H, dd, J=2.5, 8.5 Hz), 6.75 (1H,
dd, J=2.5, 8.5 Hz), 6.83 (1H, d, J=8.5 Hz), 6.88 (1H, d, J=2.5 Hz), 6.94 (1H, d, J=8.0 Hz), 6.97
(1H, d, J=8.0 Hz); 13C NMR (125 MHz, CDCl3): δ 30.2, 30.5, 37.4, 38.1, 113.0, 113.3, 114.7,
115.1, 116.9, 117.8, 123.0, 123.3, 124.0, 124.0, 127.8, 128.9, 130.0, 131.1, 131.1, 131.7, 135.0,
138.5, 140.5, 141.6, 147.9, 150.2, 153.8, 155.5; IR (ATR): 3394, 2924, 2853, 1605, 1505, 1439
cm−1; EIMS m/z (rel. int.): 422 [M]+ (100), 331 (35); HR-EIMS: [M]+ calcd for C28H22O4
422.1518; found 422.1521.
3-Methoxy-4-methoxymethoxybenzaldehyde (46)CHO

CHO
MOMCl, DIPEA

OMeOH

CH2Cl2
95%

OMe
OMOM
46

Vanilin "Y0\º¿aCAX\ (114.7 mg, 0.75 mmol) Î»THF ÈÂ (1.5 ml) !0 °C
t{N,N-3$8J[GY':Y"Q\ (260 µL, 1.51 mmol) !x·,[[3S:Y']<Y (85 µL, 1.13 mmol) !x1.5­ć¨¤2 N HCl !x
~ !n¸»!EtOAc£u ®¶!Ďč»¾ÀÞā@>
X%RcÑ Ëé ¹Ä!*WR,[P>-WH#](Hexane:EtOAc = 3:2) ãô 46 (141.5 mg, 95%) !Compound 46: colorless oil; 1H NMR (500 MHz, CDCl3): δ 3.53 (3H, s), 3.96 (3H, s), 5.34 (2H,s), 7.27 (1H, d, J=8.7 Hz), 7.44 (1H, dd, J=1.5, 8.7 Hz), 7.45 (1H, d, J=1.5 Hz), 9.88 (1H, s);
13
C NMR (125 MHz, CDCl3): δ 56.1, 56.6, 95.0, 109.5, 114.6, 126.5, 131.1, 150.0, 152.0,
191.1; IR (ATR): 2934, 1683, 1589, 1508 1466, 1424 cm−1; EIMS m/z (rel. int.): 196 [M]+ (60)45 (100); HR-EIMS: [M]+ calcd for C10H12O4 196.0736; found 196.0748.
2-Bromo-3-hydroxy-4-methoxybenzaldehyde (47)
CHO
OH
OMe
Isovanilin

Fe powder, Br 2
NaOAc
HOAc
71%

CHO
Br
OH
OMe
47

 $8CAX\ (6.00 g, 39.4 mmol) Āā@>X%R (6.50 g, 78.9 mmol) ĀāÈÂ(40 mL) ýoĄ (66.0 mg, 1.18 µmol) !x Éa[]>!Øìå (1.80mL, 41.8 mol) !30vćg`
xÅ12­ć¨¤»!x~ !n¸Ìü ¹Ä!ÛácÑ  47 (6.39 g, 71%) !64

Compound 46: white solid; 1H NMR (300 MHz, CDCl3): δ 4.01 (3H, s), 6.07 (1H, s), 6.93 (1H,d, J=8.6 Hz), 7.58 (1H, d, J=8.6 Hz), 10.26 (1H, s); 13C NMR (125 MHz, CDCl3): δ 56.6, 109.3,
112.9, 122.8, 127.2, 143.2, 151.7, 190.9; IR (ATR): 3186, 1662, 1562 cm−1; EIMS m/z (rel.
int.): 232 (90), 231 [M]+ (100), 230 (90), 229 [M]+ (100), 79 (20), 51 (10); HR-EIMS: [M]+calcd for C8H7BrO3 229.9579; found 229.9574; mp: 204.8−206.6 °C.
3-Benzyloxy-2-bromo-4-methoxybenzaldehyde (48)
CHO
Br
OH
OMe

BnBr, K 2CO 3
DMF
91%

47

CHO
Br
OBn
OMe
48

47 (4.36 g, 18.9 mmol) Íā*X%R (5.24 g, 37.9 mmol) Î»DMFÈÂ (95 mL)ìyK\3Y (2.47 mL, 20.9 mmol) !x65 °CxÐ18­ć¨¤»!x
~ !n¸»!Et2O£u ®¶!Ďč»¾ÀÞā
@>X%RcÑ Ëé ¹Ä!*WR,[P>-WH#](Hexane:EtOAc = 4:1) ãô 48 (5.50 g, 91%) !Compound 48: colorless oil; 1H NMR (500 MHz, CDCl3): δ 3.97 (3H, s), 5.06 (2H, s), 6.99 (1H,d, J=8.6 Hz), 7.37−7.43 (3H, m), 7.56 (2H, d, J=7.4 Hz), 7.77 (1H, d, J=8.6 Hz), 10.28 (1H, s);
13
C NMR (125 MHz, CDCl3): δ 56.3, 74.8, 110.9, 123.6, 126.6, 127.4, 128.3, 128.4, 128.5,
136.6, 145.1, 158.8, 191.1; IR (ATR) 2941, 2862, 1680, 1579, 1562, 1486, 1456, 1440, 1422
cm−1; EIMS m/z (rel. int.): 322 [M]+ (60), 320 [M]+ (60), 241(40), 91 (100), 65 (70); HR-EIMS:[M]+ calcd for C15H13BrO3 320.0048; found 320.0049.
3-Benzyloxy-2-bromo-4-methoxyphenylmethanol (49)
CHO
Br
OBn
OMe

OH
NaBH 4Br

THF, 99%

OBn
OMe

48

49

 "Y0\º¿a48 (1.00 g, 3.13 mmol) Î» THF ÈÂ (31 mL) ! 0 °C t{»åyM%å@>X%R (242 mg, 6.25 mmol) !xÅ 12 ­ć¨¤Ď
y"\TA%R»ÈÂ!x~ !n¸»! EtOAc £u ®
¶!Þā@>X%RcÑ Ëé ¹Ä!*WR,[P>-WH#] (Hexane:EtOAc = 2:1) ãô 49 (1.00 g, 99%) !Compound 49: colorless oil; 1H NMR (500 MHz, CDCl3): δ 2.24 (1H, s), 3.85 (3H, s), 4.67 (2H,s), 5.01 (2H, s), 6.87 (1H, d, J=8.3 Hz), 7.16 (1H, d, J=8.3 Hz), 7.33 (1H, t, J=7.4 Hz), 7.38
(2H, t, J=7.4 Hz), 7.55 (2H, d, J=7.4 Hz); 13C NMR (125 MHz, CDCl3): δ 56.1, 65.0, 74.6,
111.2, 118.8, 124.3, 128.1, 128.3, 128.4, 132.8, 137.1, 145.2, 153.2; IR (ATR): 3334, 2938,
65

1594, 1484, 1455, 1439, 1417 cm−1; EIMS m/z (rel. int.): 324 [M]+ (30), 322 [M]+ (30), 243(60), 216 (50), 214 (50), 91 (100), 65 (20); HR-EIMS: [M]+ calcd for C15H15BrO3 322.0205;
found 322.0208.
2-Benzyloxy-3-bromo-4-bromomethyl-1-methoxybenzene (50)
OH

Br

Br

CBr 4, PPh 3

Br

OBn
OMe

CH2Cl2
85%

OBn
OMe

49

50

 "Y0\º¿a49 (1.00 g, 3.09 mmol) Î» CH2Cl2 (31 mL) ÈÂ! 0 °C t{ìyÍå (1.13 g, 3.40 mmol)>XH&AYH(4H#\ (893 mg, 3.40 mmol) !x 30 vć¨¤~ ædËé ¹Ä!*WR,[P>-WH#](Hexane:Et2O = 10:1) ãô 50 (1.00 g, 85%) !Compound 38: colorless oil; 1H NMR (500 MHz, CDCl3): δ 3.88 (3H, s), 4.70 (2H, s) 5.03 (2H,s), 6.90 (1H, d, J=8.5 Hz), 7.18 (1H, d, J=8.5 Hz), 7.34 (1H, t, J=6.4 Hz), 7.39 (2H, t, J=6.4
Hz), 7.56 (2H, d, J=6.4 Hz); 13C NMR (125 MHz, CDCl3): δ 56.2, 65.2, 74.6, 111.2, 119.0,
124.4, 128.1, 128.4, 128.5, 132.8, 137.1, 145.4, 153.3; IR (ATR): 3356, 2939, 1594, 1486, 1455,
1439, 1417 cm−1; EIMS m/z (rel. int.): 388 [M]+ (20), 386 [M]+ (20), 384 [M]+ (20), 307 (60),305 (60), 216 (50), 214 (50), 91 (100); HR-EIMS: [M]+ calcd for C15H14Br2O2 383.9361; found383.9363.
Dimethyl (3-(benzyloxy)-2-bromo-4-methoxybenzyl)phosphonate (51)O
P(OMe) 2

Br
Br

P(OMe) 3

OBn
OMe

Benzene
98%

Br
OBn
OMe
51

50

 50 (2.78 g, 7.21 mmol) fX\ā>XS:Y (2.55 mL, 21.6 mmol) K\7\ÈÂ! 90 °C  12 ­ćxÐý¿ Ëé ¹Ä!*WR,[P>-WH#] (EtOAc) ãô51 (2.92 g, 98%) !Compound 51: colorless oil; 1H NMR (500 MHz, CDCl3): δ 3.40 (2H, d, J=21.5 Hz), 3.66 (3H,s), 3.68 (3H, s), 3.85 (3H, s), 5.02 (2H, s), 6.87 (1H, d, J=8.6 Hz), 7.18 (1H, dd, J=2.8, 8.6 Hz),7.31 (1H, t, J=6.9 Hz), 7.37 (2H, t, J=6.9 Hz), 7.54 (2H, d, J=6.9 Hz); 13C NMR (125 MHz,CDCl3): δ 31.4, 32.5, 52.7, 52.8, 55.9, 74.3, 111.3, 113.3, 121.0, 120.9, 121.0, 124.0, 124.0,
126.3, 126.3, 127.9, 128.2, 128.3, 136.9, 145.2, 145.2, 152.6, 152.6; IR (ATR): 2952, 1594,
1485, 1456, 1440, 1417 cm−1; EIMS m/z (rel. int.): 416 [M]+ (20), 414 [M]+ (20), 335 (60), 244(50), 91 (100); HR-EIMS: [M]+ calcd for C17H20BrO5P 414.0232; found 414.0226.

66

(E)-2-Benzyloxy-3-bromo-1-methoxy-4-(3-methoxy-4-(methoxymethoxy)styryl)benzene (52)O
P(OMe) 2

CHO

+
OMe
OMOM

MeO
NaH

Br
OBn
OMe

THF
93%

BnO
Br

51

46

OMOM
OMe
52

 "Y0\º¿a51 (477 mg, 1.15 mmol) Î»THFÈÂ (9 mL) !0 °Ct{60% »åy@>X%R (46.0 mg, 1.15 mmol) !x30vć¨¤· 46 (150
mg, 766 µmol) Î»THFÈÂ (2 mL) !xÅ7.5­ć¨¤Ďy"\
TA%R»ÈÂ!x~ !n¸»!EtOAc£u ®¶!»Ďč»¾ÀÞā@>X%RcÑ Ëé ¹Ä!*WR,[P>-WH#] (CH2Cl2:Hexane = 2:1) ãô52 (344 mg, 93%) !Compound 52: colorless oil; 1H NMR (500 MHz, CDCl3): δ 3.53 (3H, s), 3.90 (3H, s), 3.95 (3H,s), 5.04 (2H, s), 5.25 (2H, s), 6.87 (1H, d, J=16.1 Hz), 6.91 (1H, d, J=8.8 Hz), 7.06 (1H, dd,
J=1.9, 8.3 Hz), 7.09 (1H, d, J=1.9 Hz), 7.15 (1H, d, J=8.1 Hz), 7.32 (1H, d, J=16.1 Hz), 7.34
(1H, t, J=7.3 Hz), 7.40 (2H, t, J=7.3 Hz), 7.40 (1H, d, J=8.1 Hz), 7.58 (2H, d, J=7.3 Hz); 13C
NMR (125 MHz, CDCl3): δ 56.0, 56.2, 56.2, 74.6, 95.5, 109.5, 111.6, 116.3, 119.9, 120.3,
121.8, 126.2, 128.1, 128.3, 128.5, 129.5, 131.0, 132.1, 137.2, 145.3, 146.4, 149.9, 153.0; IR(ATR): 2938, 1589, 1507, 1478 cm−1; EIMS m/z (rel. int.): 486 [M]+ (80), 484 [M]+ (80), 91(100) 45 (30); HR-EIMS: [M]+ calcd for C25H25BrO5 484.0885; found 484.0893.
2-Benzyloxy-3-bromo-1-methoxy-4-(3-methoxy-4-(methoxymethoxy)phenethyl)benzene (44)MeO
MeO
TsNHNH2, NaHCO 3

BnO
Br

OMOM
OMe

EtOC 2H 4OH
79%

BnO
Br
MOMO
OMe
44

52

 52ē73.0 mg, 151 µmolĔEtOC2H4OHÈÂ (2 mL) TsNHNH2 (281 mg, 1.50 mmol) Íā»å@>X%R (126 mg, 1.50 mmol) !x135 °C14­ćxÐ×¿~ædCelite®535RVSÌü»!xEtOAc£u®¶!»Ďč»
¾À ®¶!Þā@>X%RcÑ Ëé ¹Ä!*
WR,[P>-WH#] (Hexane:Et2O = 9:1) ãô44 (58.0 mg, 79%) !Compound 44: colorless oil; 1H NMR (500 MHz, CDCl3): δ 2.82−2.85 (2H, m), 2.97−3.00 (2H,m), 3.52 (3H, s), 3.85 (3H, s), 3.85 (3H, s), 5.03 (2H, s), 5.21 (2H, s), 6.71 (1H, d, J=2.0 Hz),6.74 (1H, dd, J=2.0, 8.3 Hz), 6.80 (1H, d, J=8.5 Hz), 6.88 (1H, d, J=8.5 Hz), 7.07 (1H, d, J=8.3
Hz), 7.33 (1H, t, J=7.1 Hz), 7.39 (2H, t, J=7.1 Hz), 7.58 (2H, d, J=7.1 Hz); 13C NMR (125MHz, CDCl3): δ 36.0, 38.1, 55.8, 56.1, 56.2, 74.5, 95.7, 111.2, 112.3, 116.5, 120.5, 120.5,
67125.2, 128.0, 128.3, 128.4, 134.0, 136.1, 137.3, 144.6, 145.3, 149.5, 152.0; IR (ATR): 2937,
1593, 1506, 1476 cm−1; EIMS m/z (rel. int.): 488 [M]+ (60), 486 [M]+ (60), 230 (40), 227 (40),181 (60), 151 (50), 91 (100), 45 (60); HR-EIMS: [M]+ calcd for C25H27BrO5 486.1042; found486.1048.
5-Benzyloxy-2, 6-dimethoxy-3-methoxymethoxy-9,10-dihydrophenanthrene (53)
MeO

MeO

MeO

Pd(OAc) 2, n-Bu3P
Ag2CO 3

BnO

BnO
MeO

BnO

DMF
(0.01 M)
120 °C

MOMO

MOMO

MOMO

MeO
BnO
Br
MOMO
OMe
44

OMe
53

OMe
54

55

 "Y0\º¿a44 (15.5 mg, 31.9 µmol) Î»DMFÈÂ (3.1 mL) Íāą (26.2
mg, 95.7 µmol)ĀāDW3%R (1.4 mg, 6.39 µmol)>X-n-I:YH(4H#\ (2.6 µL,
6.38 µmol) !x120 °CxÐ12­ć¨¤~ ædCelite®535RVSÌüÌÂ!Ëé ¹Ä!*WR,[P>-WH#] (HexaneEtOAc =4:1) ãô53 (3.0 mg, 23%) 54 (2.0 mg, 15%) !Compound 53: colorless oil; 1H NMR (500 MHz, CDCl3): δ 2.72 (4H, br s) 3.36 (3H, s), 3.87
(3H, s), 3.91 (3H, s), 4.82 (2H, s), 4.97 (2H, s), 6.77 (1H, s), 6.77 (1H, d, J=8.3 Hz), 6.95 (1H,d, J=8.3 Hz), 7.26−7.30 (3H, m), 7.40 (2H, d, J=7.4 Hz), 8.26 (1H, s); 13C NMR (125 MHz,CDCl3): δ 29.7, 29.8, 55.8, 56.0, 56.1, 74.5, 95.6, 110.3, 110.9, 117.9, 123.0, 125.2, 127.8,
128.1, 128.5, 128.6, 131.4, 133.5, 137.6, 144.2, 145.2, 148.9, 152.3; IR (ATR): 2933, 2834,
1599, 1509, 1464, 1437, 1409 cm−1; EIMS m/z (rel. int.): 406 [M]+ (100), 315 (70), 283 (60),268 (50), 239 (60), 91 (40), 45 (20); HR-EIMS: [M]+ calcd for C25H26O5 406.1780; found406.1784.
Compound 54:colorless oil; 1H NMR (500 MHz, CDCl3): δ 2.92−2.95 (2H, m), 3.27−3.30 (2H,m), 3.52 (3H, s), 3.83 (3H, s), 3.91 (3H, s), 4.98 (2H, s), 5.20 (2H, s), 6.70 (1H, d, J=1.9 Hz).
6.71 (1H, dd, J=1.9, 7.5 Hz), 6.85 (1H, d, J=8.5 Hz), 6.96 (1H, d, J=8.5 Hz), 7.05 (1H, d, J=7.5
Hz), 7.26 (1H, d, J=7.5 Hz), 7.31 (1H, t, J=7.5 Hz), 7.37 (1H, t, J=7.5 Hz), 7.75 (1H, d, J=7.5
Hz); 13C NMR (125 MHz, CDCl3): δ 37.2, 35.7, 55.8, 56.1, 56.2, 69.5, 95.6, 111.2, 112.1, 116.6,
120.4, 123.5, 124.1, 125.1, 126.1, 127.1, 127.9, 130.5, 133.8, 136.1, 144.6, 145.6, 147.2, 149.6;
IR (ATR): 2927, 2852, 1725, 1595, 1513, 1464, 1417 cm−1; EIMS m/z (rel. int.): 406 [M]+ (60),225 (100), 165 (50); HR-EIMS: [M]+ calcd for C25H26O5 406.1780; found 406.1786.
Compound 55: colorless oil; 1H NMR (500 MHz, CDCl3): δ 2.82 (4H, s), 3.53 (3H, s), 3.84 (3H,s), 3.88 (3H, s), 5.12 (2H, s), 5.22 (2H, s), 6.66 (1H, d, J=1.9 Hz), 6.68 (1H, dd, J=1.9, 8.0 Hz),6.73 (1H, d, J=1.9 Hz), 6.74 (1H, d, J=1.9, 8.3 Hz), 6.83 (1H, d, J=8.0 Hz), 7.07 (1H, d, J=8.3
Hz), 7.32 (1H, t, J=7.6 Hz), 7.83 (2H, t, J=7.6 Hz), 7.46 (2H, t, J=7.6 Hz); 13C NMR (125 MHz,CDCl3): δ 37.4, 37.6, 55.7, 55.8, 56,0, 56.1, 71.1, 95.6, 111.9, 112.3, 112.3, 114.9, 116.5, 120.5,
121.0, 127.3, 127.7, 128.4, 134.2, 136.2, 137.3, 144.6, 147.9, 148.0, 149.5; IR (ATR): 2932,
681589, 1510, 1454, 1419 cm−1; EIMS m/z (rel. int.): 408 [M]+ (100), 227 (100), 181 (80), 151(40), 91 (90), 45 (20); HR-EIMS: [M]+ calcd for C25H28O5 408.1937; found 408.1945.
3,7-Dimethoxy-6-methoxymethoxy-9,10-dihydrophenanthren-4-ol (56)
MeO

MeO

BnO

H 2, Pd(OH) 2

MOMO

CHCl 3
97%
OMe

HO

MOMO
OMe
56

53

 53 (32.1 mg, 79.1 µmol) CHCl3ÈÂ (1 mL)  Pd(OH)2C (3.0 mg) !x»åº¿a24­ćÊ ¨¤~ ædCelite®535RVSÌüÌÂ!Ëé ¹Ä!*WR,[P>-WH#] (Hexane:EtOAc = 4:1) ãô56 (24.2 mg,
97%) !
Compound 56: colorless oil; 1H NMR (500 MHz, CDCl3): δ 2.74 (4H, br s) 3.55 (3H, s), 3.90
(3H, s), 3.91 (3H, s) 5.28 (2H, s), 6.27 (1H, s), 6.71 (1H, d, J=8.1 Hz), 6.72 (1H, d, J=8.1 Hz),6.78 (1H, s), 8.32 (1H, s); 13C NMR (125 MHz, CDCl3): δ 29.8, 29.8, 55.9, 56.3, 56.4, 95.9,
108.4, 111.2, 117.5, 118.1, 120.5, 125.4, 131.5, 133.1, 142.8, 144.2, 145.7, 148.5; IR (ATR):
3485, 2938, 2836, 1601, 1509, 1448, 1400 cm−1; EIMS m/z (rel. int.): 316 [M]+ (100), 284 (20),211 (20), 45(20); HR-EIMS: [M]+ calcd for C18H20O5 316.1311; found 316.1309.
4-((3,7-Dimethoxy-6-(methoxymethoxy)-9,10-dihydrophenanthren-4-yl)oxy)benzaldehyde (57)MeO

p-Bromobenzaldehyde
CuO, K 2CO 3

HO

Pyridine
65%

MOMO

OHC

MeO
O
MOMO

OMe

OMe

56

57

"Y0\º¿ap-I[TK\5"Y=E? (43.1 mg, 233 µmol)Íā*X%R (42.9
mg, 311 µmol) āyĆ (II) (18.5 mg, 233 µmol) Î»GX3\ÈÂ (1 mL)  56
(49.2 mg, 156 µmol) Î»GX3\ÈÂ (0.5 mL) !x125 °C24­ćxÐ×¿
~ ædCelite®535RVSÌüÌÂ!Ëé ¹Ä!*WR,[
P>-WH#] (Hexane:EtOAc = 4:1) ãô57 (41.2 mg, 65%) !Compound 57: colorless oil; 1H NMR (500 MHz, CDCl3): δ 2.76−2.81 (4H, m), 3.41 (3H, s),
3.76 (3H, s), 3.86 (3H, s), 5.09 (2H, s), 6.73 (1H, s), 6.86 (1H, d, J=8.1 Hz), 6.96 (2H, d, J=8.4
Hz), 7.14 (1H, d, J=8.1 Hz), 7.75 (2H, d, J=8.6 Hz), 8.05 (1H, s), 9.84 (1H, s); 13C NMR (125MHz, CDCl3): δ 29.6, 29.8, 55.7, 56.0, 56.1, 95.8, 110.5, 111.1, 115.4, 116.8, 123.8, 125.1,
128.7, 130.6, 131.8, 131.8, 133.6, 139.0, 144.8, 149.0, 151.3, 163.9, 190.8; IR (ATR): 2941,
2836, 1692, 1596, 1508, 1436 cm−1; EIMS m/z (rel. int.): 421 (50), 420 [M]+ (100), 390 (50), 45(20); HR-EIMS: [M]+ calcd for C25H24O6 420.1573; found 420.1577.
69

(E)-5-(4-(2-Bromo-5-methoxystyryl)phenoxy)-2,6-dimethoxy-3-(methoxymethoxy)-9,10-dihydrophenanthrene (58)
OHC

OMe

MeO

MeO

OMe
O

O
P(OMe) 2

+

NaH

Br

O

THF, 97%

Br

MOMO
OMe

MOMO

7

57

OMe

58

 "Y0\º¿a7 (21.4 mg, 69.4 µmol) Î» THF ÈÂ (0.25 mL) ! 0 °C t{
60 % »åy@>X%R (4.1 mg, 104 µmol) !x 30 vć¨¤· 57 (14.6 mg,
34.7 µmol) Î» THF ÈÂ (0.1 mL) !xÅ 24 ­ć¨¤Ďy"\
TA%R»ÈÂ!x~ !n¸»! EtOAc £u®¶!»Ďč»¾À ®¶!Þā@>X%RcÑ Ëé ¹Ä!
*WR,[P>-WH#] (CH2Cl2:Hexane = 1:1) ãô 58 (20.3 mg, 97%) !

Compound 58: colorless oil; 1H NMR (500 MHz, CDCl3): δ 2.75−2.79 (4H, m), 3.42 (3H, s),
3.76 (3H, s), 3.82 (3H, s), 3.85 (3H, s), 5.10 (2H, s), 6.67 (1H, dd, J=3.0, 8.8 Hz), 6.72 (1H, s),
6.84 (2H, d, J=8.8 Hz), 6.84 (1H, d, J=8.3 Hz), 6.91 (1H, d, J=16.1 Hz), 7.10 (1H, d, J=8.8 Hz),7.12 (1H, d, J=3.0 Hz), 7.22 (1H, d, J=16.1 Hz), 7.38 (2H, d, J=8.8 Hz), 7.43 (1H, d, J=8.3 Hz),8.12 (1H, s); 13C NMR (125 MHz, CDCl3): δ 29.6, 29.9, 55.5, 55.7, 56.0, 56.2, 95.9, 110.5,
111.1, 111.5, 114.7, 114.8, 115.2, 117.2, 124.2, 124.6, 125.5, 128.0, 128.9, 130.4, 131.1, 131.7,
133.5, 133.6, 138.1, 139.7, 144.7, 149.0, 151.7, 158.0, 159.0; IR (ATR): 2939, 2835, 1594,
1505, 1458 cm−1; EIMS m/z (rel. int.): 604 [M]+ (100), 602 [M]+ (100), 574 (20), 572 (20), 478(10), 446 (10), 357 (10), 235 (10), 165 (10), 45 (20); HR-EIMS: [M]+ calcd for C33H31BrO6
602.1304; found 602.1306.
5-(4-(2-Bromo-5-methoxyphenethyl)phenoxy)-2,6-dimethoxy-3-(methoxymethoxy)-9,10-dihydrophenanthrene (59)
OMe

OMe
MeO

Br

MeO
TsNHNH2, NaHCO 3

O

EtOC 2H 4OH
98%

MOMO

Br

O

MOMO

OMe

OMe

58

59

 58ē46.7 mg, 77.6 µmolĔ EtOC2H4OH ÈÂ (1 mL)  TsNHNH2 (144 mg, 776 µmol) Íā»å@>X%R (65.1 mg, 776 µmol) !x135 °C  12 ­ćxÐ×¿~æd»!x»! Et2O £u®¶!»Ďč»¾ÀÞā@>70

X%RcÑ Ëé ¹Ä!*WR,[P>-WH#] (Hexane:Et2O= 9:1) ãô 59 (46.0 mg, 98%) !Compound 59: colorless oil; 1H NMR (500 MHz, CDCl3): δ 2.74−2.79 (6H, m), 2.88−2.90 (2H,m), 3.41 (3H, s), 3.69 (3H, s), 3.75 (3H, s), 3.85 (3H, s), 5.09 (2H, s), 6.61 (1H, dd, J=3.0, 8.6
Hz), 6.65 (1H, d, J=3.0 Hz), 6.71 (1H, s), 6.75 (2H, d, J=8.6 Hz), 6.83 (1H, d, J=8.2 Hz), 7.02
(2H, d, J=8.6 Hz), 7.07 (1H, d, J=8.2 Hz), 7.39 (1H, d, J=8.6 Hz), 8.15 (1H, s); 13C NMR (125MHz, CDCl3): δ 29.7, 29.9, 35.3, 38.7, 55.3, 55.7, 56.0, 56.2, 95.9, 110.6, 111.0, 113.4, 114.6,
114.8, 116.0, 117.4, 124.4, 124.5, 129.0, 129.2, 131.6, 133.2, 133.5, 134.1, 140.0, 142.0, 144.6,
148.9, 151.9, 156.1, 158.8; IR (ATR): 2934, 2834, 1601, 1570, 1504, 1464, 1437, 1411 cm−1;
EIMS m/z (rel. int.): 606 [M]+ (100), 604 [M]+ (100), 560 (20), 480 (20), 405 (20), 373 (30),361 (40), 239 (20), 45 (20); HR-EIMS: [M]+ calcd for C33H33BrO6 604.1461; found 604.1465.
5-(4-(2-Bromo-5-methoxyphenethyl)phenoxy)-2,6-dimethoxy-9,10-dihydrophenanthren-3-ol
(60)
OMe

OMe
MeO

Br

MeO
Dowex ® 50WX2-100

O

Br

O

MeOH/EtOAc = 2 : 1
70 °C, 96%

MOMO

HO

OMe

OMe

59

60

 59 (288 mg, 476 µmol)  MeOHEtOAc = 2:1 ÈÂ (5 mL)  Dowex® 50WX2-100 !
x70 °C xÐ12 ­ć¨¤~ ædCelite®535RVS ÌüÌÂ!
Ëé ¹Ä!*WR,[P>-WH#] (HexaneEtOAc = 4:1) ãô
 60 (256 mg, 96%) !Compound 60: colorless oil; 1H NMR (500 MHz, CDCl3): δ 2.71−2.79 (6H, m), 2.89−2.92 (2H,m), 3.69 (3H, s), 3.74 (3H, s), 3.86 (3H, s), 5.31 (1H, s), 6.61 (1H, dd, J=2.9, 8.6 Hz), 6.64 (1H,d, J=2.9 Hz), 6.68 (1H, s), 6.74 (2H, d, J=8.5 Hz), 6.83 (1H, d, J=8.5 Hz), 7.02 (2H, d, J=8.5
Hz), 7.06 (1H, d, J=8.6 Hz), 7.39 (1H, d, J=8.5 Hz), 7.87 (1H, s); 13C NMR (125 MHz, CDCl3):
δ 29.9, 29.9, 35.3, 38.7, 55.4, 55.8, 56.3, 110.0, 110.7, 113.5, 114.8, 114.8, 115.0, 115.9, 124.2,
124.9, 129.0, 129.3, 131.2, 131.8, 133.2, 134.0, 140.5, 142.0, 143.6, 145.6, 151.9, 156.2, 158.8;
IR (ATR): 3517, 2935, 1592, 1505, 1460, 1437 cm−1; EIMS m/z (rel. int.): 562 [M]+ (50), 560[M]+ (50), 480 (10), 361 (100); HR-EIMS: [M]+ calcd for C31H29BrO5 560.1198; found560.1197.

71

2,6-dimethoxy-5-(4-(5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)phenoxy)-9,10-dihydrophenanthren-3-ol (61)OMe

OMe
Pd(PPh 3)4
B 2Pin 2
K 3PO 4MeO
Br

O

Dioxane
95%

HO

MeO
B
O

O

O

HO

OMe

OMe

60

61

 "Y0\º¿a60 (256 mg, 456 µmol) <>W+4>XH&AYH(4H#\DW
3%R (52.7 mg, 45.6 µmol)F4(G@/W]>)3N[\ (236 mg, 912 µmol) X\ā_*X%R (291 mg, 1.37 mmol) Î»3)+1\ÈÂ (5 mL) ! 100 °C xÐ
16.5 ­ć¨¤~ ædCelite®535RVS ÌüÌÂ!Ëé ¹
Ä!*WR,[P>-WH#] (Hexane:Et2O = 3:2) ãô 61 (263 mg, 95%) !

Compound 61: colorless oil; 1H NMR (500 MHz, CDCl3): δ 1.34 (12H, s), 2.71−2.78 (6H, m),
3.05−3.09 (2H, m), 3.74 (3H, s), 3.76 (3H, s), 3.86 (3H, s), 5.34 (1H, s), 6.66 (1H, d, J=2.5 Hz),6.68 (1H, s), 6.71 (1H, dd, J=2.5, 8.5 Hz), 6.74 (2H, d, J=8.5 Hz), 6.83 (1H, d, J=8.0 Hz), 7.07
(1H, d, J=8.0 Hz), 7.08 (2H, d, J=8.5 Hz), 7.76 (1H, d, J=8.5 Hz), 7.89 (1H, s); 13C NMR (125MHz): δ 24.9, 29.9, 29.9, 38.9, 39.0, 55.0, 55.8, 56.3, 83.2, 110.0, 110.6, 110.8, 114.6, 114.6,
115.1, 115.1, 124.1, 129.0, 129.3, 131.1, 131.8, 135.5, 138.2, 140.6, 143.6, 145.6, 151.7, 152.0,
156.0, 161.8; IR (ATR): 3522, 2934, 1601, 1567, 1567, 1505, 1436 cm−1; EIMS m/z (rel. int.):
608 [M]+ (100), 361 (100); HR-EIMS: [M]+ calcd for C37H41BO7 608.2945; found 608. 2952.
2,6-Dimethoxy-5-(4-(5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)phenoxy)-9,10-dihydrophenanthren-3-yl trifluoromethanesulfonate (45)
OMe

OMe
MeO

B
O

O

O

MeO

PhNTf 2Cs2CO 3
THF
77%

B
O

O

O

HO

TfO

OMe

OMe
45

61

 "Y0\º¿a61 (190 mg, 313 µmol) Î» THF ÈÂ (3 mL)  N-H&AY>X
HY)[S9\4YM\$Q? (224 mg, 626 µmol) Íā62%R (153 mg, 470µmol) !xÅ 27 ­ć¨¤Ďy"\TA%R»ÈÂ!x~ !n¸»! Et2O £u®¶!»Ďč»¾À ®¶!Þā@>X%RcÑ Ëé ¹Ä!*WR,[P>-WH#](Hexane:EtOAc = 4:1) ãô 45 (180 mg, 77%) !Compound 45: colorless oil; 1H NMR (500 MHz, CDCl3): δ 1.33 (12H, s), 2.73−2.76 (2H, m),72

2.81 (4H, br s), 3.05−3.09 (2H, m), 3.75 (3H, s), 3.77 (3H, s), 3.89 (3H, s), 6.68 (1H, d, J=2.5
Hz), 6.71−6.74 (3H, m), 6.84 (1H, s), 6.88 (1H, d, J=8.3 Hz), 7.09 (1H, d, J=8.0 Hz), 7.13 (2H,d, J=9.0 Hz), 7.77 (1H, d, J=8.3 Hz), 8.12 (1H, s); 13C NMR (125 MHz, CDCl3): δ 24.9, 29.0,
30.3, 38.9, 39.0, 55.0, 56.1, 56.3, 83.2, 110.6, 111.5, 112.2, 114.4, 115.1, 117.4, 119.9, 122.4,
124.5, 125.0, 127.6, 129.3, 131.2, 136.0, 137.0, 138.3, 140.3, 140.4, 150.1, 151.6, 152.0, 155.6,
161.8; IR (ATR): 2937, 1604, 1504, 1418 cm−1; FABMS m/z (rel. int.): 779 [M+Na]+, 740 [M]+(20), 641 (10), 493 (20); HR-FABMS: [M]+ calcd for C38H40F3O9SB 740.2438; found740.2441.
Trimethyl cavicularin (37)
OMe
MeO

MeO
B
O

O

O

O

Pd 2(dba) 3, (S)-(−)-BINAPK 3PO 4
DMF
100 °C2%, 18%ee

TfO
OMe
45

MeO
MeO
37

 "Y0\º¿a45 (13.9 mg, 18.8 µmol) Î» DMF ÈÂ (4 mL) >X4(3K\
3X=\"6>\)3DW3%R (1.7 mg, 1.88 µmol)(S)-(−)-BINAP (2.3 mg, 3.75 µmol)
X\ā_*X%R (11.9 mg, 56.3 µmol) !x100 °C xÐ12 ­ć2]Y?:
U]Is¨¤~ ædCelite®535RVS ÌüÌÂ!>Y'\r¼ Ëé ¹Ä!*WR,[P>-WH#] (Hexane:EtOAc = 3:1) ãô
 37 (0.2 mg, 2%) !Compound 37: colorless oil; 1H NMR (500 MHz, CDCl3): δ 2.18 (1H, ddd, J=3.5, 13.0, 13.0Hz), 2.36 (1H, dd, J=7.5, 7.5 Hz), 2.54 (1H, ddd, J=3.5, 13.0, 13.0 Hz), 2.67−2.93 (5H, m),
3.72 (3H, s), 3.87 (3H, s), 3.93 (3H, s), 5.98 (1H, dd, J=2.5, 8.5 Hz), 6.08 (1H, dd, J=2.0, 8.5
Hz), 6.37 (1H, dd, J=2.0, 8.0 Hz), 6.54 (1H, s), 6.63 (1H, s), 6.72 (1H, dd, J=2.5, 8.0 Hz), 6.74
(1H, dd, J=2.5, 8.5 Hz), 6.79 (1H, d, J=8.5 Hz), 6.87 (1H, d, J=2.5 Hz), 6.95 (1H, d, J=8.0 Hz),7.03 (1H, d, J=8.0 Hz); 13C NMR (125 MHz, CDCl3): δ 29.7, 30.5, 31.1, 37.8, 38.1, 55.2, 56.7,
108.8, 110.6, 111.3, 114.0, 115.3, 117.8, 122.1, 122.1, 124.3, 126.9, 127.1, 129.6, 130.2, 131.7,
132.1, 132.6, 134.4, 139.6, 141.1, 142.1, 151.7, 154.2, 154.3, 158.6; IR (ATR): 2919, 2844,
1602, 1504, 1461 cm−1; EIMS m/z (rel. int.): 464 [M]+ (100), 373 (40); HR-EIMS: [M]+ calcd
for C31H28O4 464.1088; found 464.1982; 18%ee.

73Column : 4.6 x 150 mm, Kromasil 3-CelluCoat
Solvent : Hex : i-PrOH
Flow rate : 1 mL/min
MeO
Detector : UV 254 nm
O

OMe

MeO
(±)-37

Column : 4.6 x 150 mm, Kromasil 3-CelluCoat
Solvent : Hex : i-PrOH
Flow rate : 1 mL/min
Detector : UV 254 nm
MeO

MeO

O

O

or

MeO

MeO

MeO

MeO

(−)-37(+)-3710’-Bromo-dimethyl-(S)-(+)-naproxen-riccardin C (65)
OMe

OMe

O

O
(S)-(+)-Naproxen
EDC, DMAPBr

BrCH2Cl2
78%

MeO

MeO
O

HO

MeO

38

O

65

 "Y0\º¿a38 (3.9 mg, 7.36 µmol)N,N-3S:Y-4-"QBGX3\ (1.5 mg, 12.2µmol)EDC (2.1 mg, 11.4 µmol)  (S)-(+)-@J[+6\ (2.5 mg, 11.4 µmol) Î»
CH2Cl2 ÈÂ (73 µL) !Å 30 vć¨¤Ďy"\TA%R»ÈÂ!x~!n¸»! CH2Cl2 £u®¶!»Ďč»¾À ¹Ä
!*WR,[P>-WH#] (Hexane:Et2O = 1:1) ãô 65 (4.3 mg, 78%) !3"
4<Z)P]ÃÒ
Compound 65: colorless oil; 1H NMR (500 MHz, CDCl3): δ 1.46 (3H, d, J=7.5 Hz), 1.47 (3H, d,
J =7.5 Hz), 2.43−2.47 (2H, m), 2.57−2.71 (7H, m), 2.78−2.86 (5H, m), 3.00−3.06 (2H, m), 3.64
(3H, s), 3.79 (1H, q, J=7.0 Hz), 3.83 (3H, s), 3.88 (1H, q, J=7.0 Hz), 3.90 (3H, s), 3.93 (3H, s),
3.94 (3H, s), 3.95 (3H, s), 5.26 (1H, d, J=2.0 Hz), 5.29 (1H, d, J=2.0 Hz), 6.35 (1H, d, J=2.5
Hz), 6.45 (1H, dd, J=2.6, 8.4 Hz), 6.50 (1H, s), 6.60−6.66 (3H, m), 6.71−6.81 (11H, m), 6.85
(1H, d, J =8.3 Hz), 6.88 (1H, d, J=8.3 Hz), 6.94 (1H, d, J=8.3 Hz), 7.09 (1H, dd, J =1.7, 8.4
Hz), 7.13−7.16 (2H, m), 7.18 (1H, s), 7.23−7.26 (2H, m), 7.40 (1H, s), 7.53−7.54 (2H, m), 7.60
(1H, d, J=8.5 Hz), 7.64 (2H, d, J=9.0 Hz), 7.65 (2H, d, J=9.0 Hz); 13C NMR (125 MHz,CDCl3): δ 18.3, 18,6, 35.0, 35.2, 36.2, 36.4, 37.3, 38.0, 38.1, 45.4, 45.5, 55.0, 55.0, 55.2, 55.3,
7455.3, 56.2, 105.5, 105.6, 111.4, 111.6, 111.9, 112.0, 115.2, 115.4, 115.5, 118.9, 119.0 121.3,
121.4, 121.6 122.3, 122.6, 122.6, 124.7, 124.8, 124.9, 125.9, 126.0, 126.1, 127.2, 127.3, 127.4,
128.8, 129.3, 129.3, 129.4, 125.0, 131.7, 132.0, 133.2, 133.7, 133.8, 133.9, 134.5, 134.5, 136.4,
136.6, 139.4, 139.5, 140.5, 140,5, 142.3, 142.7, 146.7, 146.8, 147.0, 149.2, 149.2, 152.7, 152.9,
157.6, 157.7, 159.4, 159.7, 172.7, 172.8; IR (ATR): 2933, 2836, 1751, 1633, 1606, 1505, 1473,
1420 cm−1; EIMS m/z (rel. int.): 744 [M]+ (50), 742 [M]+ (40), 532 (20), 530 (20), 450 (30),212 (50), 185 (100); HR-EIMS: [M]+ calcd for C44H39O6Br 742.1930; found 742. 1925.
10’-Iodo-dimethyl-(S)-(+)-naproxen-riccardin C (66)
OMe

OMe

O

O
(S)-(+)-Naproxen
EDC, DMAPI

I
CH2Cl2
68%

MeO

MeO
O

HO

MeO

40

O

66

 "Y0\º¿a40 (12.0 mg, 26.5 µmol)N,N-3S:Y-4-"QBGX3\ (0.5 mg,
3.59 µmol)EDC (5.2 mg, 26.9 µmol)  (S)-(+)-@J[+6\ (6.2 mg, 26.9 µmol) Î»
CH2Cl2 ÈÂ (180 µL) !Å 24 ­ć¨¤Ďy"\TA%R»ÈÂ!x~ !n¸»! CH2Cl2 £u®¶!»Ďč»¾À ¹
Ä!*WR,[P>-WH#] (Hexane:EtOAc = 3:1) ãô 66 (9.7 mg, 68%) !
3"4<Z)P]ÃÒ
Compound 66: colorless oil; 1H NMR (500 MHz, CDCl3): δ 1.46 (3H, d, J=7.1 Hz), 1.46 (3H, d,
J =7.1 Hz), 2.40−2.42 (2H, m), 2.53−2.64 (2H, m), 2.53−2.64 (4H, m), 2.70−2.88 (10H, m),
3.64 (3H, s), 3.77−3.81 (1H, m), 3.83−3.89 (1H, m), 3.84 (3H, s), 3.92 (3H, s), 3.93 (3H, s),
3.94 (3H, s), 3.95 (3H, s), 5.23 (1H, d, J=2.0 Hz), 5.25 (1H, d, J=2.0 Hz), 6.36 (1H, d, J=2.5
Hz), 6.49 (1H, dd, J=2.5, 8.4 Hz), 6.50 (1H, s), 6.61 (1H, s), 6.30−6.89 (14H, m), 6.88 (1H, t,
J=8.5 Hz), 6.95 (1H, d, J=8.3 Hz), 7.06 (1H, d, J=2.0, 8.6 Hz), 7.11−7.17 (4H, m), 7.39 (1H, s),7.53−7.54 (3H, m), 7.60 (1H, d, J=9.1 Hz), 7.64 (2H, t, J=8.5 Hz); 13C NMR (125 MHz,CDCl3): δ 18.3, 18.7, 21.5, 35.0, 35.3, 36.6, 36.8, 38.0, 38.1, 41.3, 45.4, 45.5, 55.0, 55.0, 55.3,
55.3, 56.2, 56.2, 97.7, 97.9, 105.5, 105.6, 111.4, 111.6, 112.0, 112.1, 115.1, 115.5, 115.5, 115.6,
118.9, 119.0, 121.8, 122.3, 122.4, 122.7, 122.7, 123.7, 123.8, 125.3, 125.9, 126.0, 126.0, 126.1,
126.1, 127.2, 127.3, 127.4, 127.7, 128.9, 129.1, 129.3, 129.3, 129.6, 131.8, 132.1, 132.9, 133.7,
133.8, 133.9, 134.2, 134.5, 134.6, 137.9, 139.4, 139.6, 142.3, 142.7, 143.0, 143.3, 144.0, 147.0,
147.8, 147.9, 149.3, 149.3, 152.6, 152.8, 157.6, 157.7, 159.4, 159.7, 172.5, 172.7; IR (ATR):
2933, 2835, 1750, 1633, 1605, 1505, 1485, 1469, 1442, 1420 cm−1; EIMS m/z (rel. int.): 790[M]+ (40), 578 (10), 450 (10), 212 (30), 185 (100), 44 (30); HR-EIMS: [M]+ calcd for
C44H39O6I 790.1791; found 790.1797.

75

Dimethyl-(S)-(+)-naproxen-cavicularin (67)
OMe
O

I
MeO
O

MeO

O

O

Pd(OAc) 2, n-Bu3P
Ag2CO 3
DMF
78%

O

MeO

MeO

MeO
O

MeO

O

O

MeO

O

MeO
67

66

68

 "Y0\º¿a66 (2.6 mg, 3.29 µmol) Î» DMF ÈÂ (500 µL) Íāą (1.0 mg,
3.62 µmol)ĀāDW3%R (0.15 mg, 0.658 µmol)>X-n-I:YH(4H#\ (0.14 µL,
0.658 µmol) !x120 °C xÐ6 ­ć¨¤~ ædCelite®535RVS ÌüÌÂ!Ëé ¹Ä!*WR,[P>-WH#] (HexaneEt2O =1:1) ãô 67 (0.9 mg, 41%)  68 (0.8 mg, 37%) !Compound 67: colorless oil; 1H NMR (500 MHz, CDCl3): δ 1.40 (3H, d, J=7.0 Hz), 2.03−2.09(2H, m), 2.28−2.36 (2H, m), 2.62−2.76 (4H, m), 3.68 (3H, s), 3.79 (1H, q, J=7.0 Hz), 3.92 (3H,s), 3.96 (3H, s), 5.94−5.98 (2H, m), 6.15 (1H, d, J=2.2 Hz), 6.32 (1H, br d, J=8.5 Hz), 6.56 (1H,s), 6.59 (1H, dd, J=2.2, 8.5 Hz), 6.65 (1H, dd, J=2.2, 8.5 Hz), 6.70 (1H, d, J=8.5 Hz), 6.79 (1H,s), 6.92 (1H, d, J=8.5 Hz), 7.00−7.03 (2H, m), 7.12 (1H, br s), 7.16 (1H, dd, J=2.0, 8.5 Hz),7.39 (1H, s), 7.52 (1H, br d, J=8.5 Hz), 7.62 (1H, br d, J=8.5 Hz); 13C NMR (125 MHz,CDCl3): δ 18.5, 29.7, 30.2, 30.3, 37.3, 37.9, 45.5, 54.9, 55.3, 56.7, 105.6, 111.0, 111.4, 114.2,
114.8, 117.8, 118.8, 119.8, 122.2, 123.7, 125.8, 125.9, 127.1, 127.1, 128.8, 129.3, 129.4, 129.7,
130.2, 130.8, 132.3 133.1, 133.6, 134.4, 134.7, 139.1, 140.8, 141.6, 145.5, 151.6, 154.3, 157.5,
158.4, 172.3; IR (ATR): 2926, 2844, 1751, 1605, 1504, 1484, 1467, 1439, 1416 cm−1; EIMS
m/z (rel. int.): 662 [M]+ (50), 450 (100), 212 (30), 185 (100); HR-EIMS: [M]+ calcd for
C44H38O6 662.2668; found 662.2674; [α]D25= +30.0 (c=0.500, CHCl3).
Compound 68: colorless oil; colorless oil; 1H NMR (500 MHz, CDCl3): δ 1.33 (3H, d, J=7.4
Hz), 2.18 (1H, dt, J=3.7, 13.0 Hz), 2.44 (1H, dt, J=3.4, 12.2 Hz), 2.59−2.81 (6H, m), 3.69 (1H,q, J=7.4 Hz), 3.85 (3H, s), 3.93 (3H, s), 3.93 (3H, s), 5.99 (1H, dd, J=2.5, 8.5 Hz), 6.05 (1H, dd,
J=1.9, 8.3 Hz), 6.35 (1H, dd, J=2.2, 8.3 Hz), 6.62 (1H, s), 6.65 (1H, d, J=2.5 Hz), 6.70−6.74(3H, m), 6.79 (1H, d, J=8.5 Hz), 6.93 (1H, d, J=8.3 Hz), 7.02 (1H, d, J=8,3 Hz), 7,12 (1H, d,
J=2.2 Hz), 7.15 (1H, dd, J=2.5, 8.8 Hz), 7.19 (1H, d, J=8.6 Hz), 7.51 (1H, s), 7.63 (1H, d, J=8.3
Hz), 7.76 (1H, d, J=8.8 Hz); IR (ATR): 2927, 2849, 1750, 1606, 1505, 1487, 1418 cm−1; EIMS
m/z (rel. int.): 662 [M]+ (40), 450 (100), 359 (10), 212 (30), 185 (90); HR-EIMS: [M]+ calcd for
C44H38O6 662.2668; found 662.2677; [α]D27= −10.4 (c=0.500, CHCl3).

76

Dimethylcavicularin (32)
MeO

MeO

O

O
LiAlH 4

MeO
O
MeO

MeO

THF, 0 °C
88%

O

HO

32

67

 "Y0\º¿a67 (0.5 mg, 0.755 µmol) Î» THF ÈÂ (200 µL) ! 0 °C t{»åyX:%R"YQA%R (0.1 mg, 2.64 µmol) !x30 vć¨¤ÿÝā@>X%R*X%R»Ò»ÈÂ!x~ !n¸»! Et2O £u®¶!
»Ďč»¾À ®¶!Þā@>X%RcÑ Ëé ¹Ä!*WR,[P>-WH#] (Hexane: Et2O = 1:1) ãô 32 (0.3 mg,
88%) !
Compound 32: colorless oil; 1H NMR (500 MHz, CDCl3): δ 2.28 (1H, ddd, J=3.7, 12.4, 12.7
Hz), 2.55 (1H, ddd, J=3.4, 12.4, 12.5 Hz), 2.62−2.80 (4H, m), 2.92 (1H, ddd, J=3.4, 3.7, 12.2
Hz), 2.98 (1H, ddd, J=3.4, 3.7, 12.7 Hz), 3.90 (3H, s), 3.93 (3H, s), 4.76 (1H, s), 6.03 (1H, dd,
J=2.5, 8.3 Hz), 6.09 (1H, dd, J=2.0, 8.3 Hz), 6.23 (1H, dd, J=2.0, 8.6 Hz), 6.52 (1H, s), 6.68
(1H, s), 6.73 (1H, dd, J=2.5, 8.3 Hz), 6.83 (1H, dd, J=2.5, 8.3 Hz), 6.87−6.92 (3H, m), 7.03 (1H,d, J=8.3 Hz); 13C NMR (125 MHz, CDCl3): δ 30.4, 30.6, 37.7, 38.2, 55.3, 56.7, 110.7, 112.9,
113.4, 114.4, 115.9, 117.9, 122.3, 124.2, 124.3, 124.3, 127.4, 128.9, 129.9, 131.4, 131.5, 132.8,
133.9, 140.4, 141.1, 141.4, 150.2, 151.7, 154.5, 159.5; IR (ATR): 3425, 2929, 2855, 1604, 1565,
1505, 1420 cm−1; EIMS m/z (rel. int.): 450 [M]+ (100), 359 (50), 225 (10); HR-EIMS: [M]+calcd for C30H26O4 450.1831; found 450.1840; [α]D21= +117.2 (c=0.767, CHCl3).
(+)-Cavicularin (2)
MeO

HO

O

O
BBr 3

MeO
HO

CH2Cl2
72%

32

HO
HO

(+)-Cavicularin (2) 32 (1.8 mg, 4.00 µmol) Î»CH2Cl2 ÈÂ (1 mL) !0 °Ct{_ìyM%å
(10.2 µL, 10.2 µmol, 1M in CH2Cl2) !x24­ć¨¤»!x~ !n¸»!CH2Cl2£u ®¶!Ďč»¾ÀÞā@>X%RcÑËé ¹Ä!*WR,[P>-WH#] (Hexane:EtOAc = 7:3) ãô (+)-cavicularin (2) (1.2 mg, 72%) !Cavicularin (2): colorless oil; [α]D22= +115.7 (c=0.700, MeOH). 97.9%ee.

77Column : 4.6 x 150 mm, Kromasil 3-CelluCoat
Solvent : Hex : i-PrOH
Flow rate : 1 mL/min
Detector : UV 254 nm
HO
O

OH

HO

(±)-Cavicularin (2)Column : 4.6 x 150 mm, Kromasil 3-CelluCoat
Solvent : Hex : i-PrOH
Flow rate : 1 mL/min
Detector : UV 254 nm
HO
O
HO
HO
(+)-Cavicularin (2)

78

%
1) , (&, #)" (1982).

2) a) Y. Asakawa, “Progress in the Chemistry of Organic Natural Products” eds. W. Herz, H.
Grisebach, G. W. Kirby, Springer−Verlag, New York, 42, 1−285 (1982).
b) Y. Asakawa, “Bryophytes, Their Chemistry and Chemical Taxonomy” eds. H. D.
Zinsmeister, R. Mues, Oxford University Press, Oxford, 369−435 (1990).
c) Y. Asakawa, “Bryophyte Development: Physiology and Biochemistry” eds. R. N.
 

Chopra, S. C. Bhatla, CRC Press, Boca Raton, 260−287 (1990).
d) Y. Asakawa, “Progress in the Chemistry of Organic Natural Products” eds. W. Herz, H.
Grisebach, G. W. Kirby, Springer−Verlag, New York, 65, 1−618 (1995).
e) Y. Asakawa, A. Ludwiczuk, F. Nagashima. “Progress in the Chemistry of Organic
Natural Products” eds. A. D. Kinghorn, H. Falk, J. Kobayashi, Springer−Verlag, New
York, 95, 1−796 (2013).
f) S. Friederich, M. Rueffer, Y. Asakawa, M. H. Zenk, Phytochemistry, 52, 1195−1202(1999).
g) S. Friederich, U. H. Maier, B. Deus−Meumanr, Y. Asakawa, M. H. Zenk,
Phytochemistry, 50, 589−598 (1999).

3) T. Eicher, S. Fey, W. Puhl, E. Buchel, A. Speicher, Eur. J. Org. Chem., 877−878 (1998).
4) Y. Fukuyama, M. Kodama, Y. Asakawa, , 58, 654−665 (2000).

5) Y. Asakawa, M. Toyota, R. Matsuda, K. Takikawa, T. Takemoto, Phytochemistry, 22,1413−1415 (1983).
6) Y. Asakawa, R. Matsuda, Phytochemistry, 21, 2143−2144 (1982).
7) Y. Asakawa, M. Tori, K. Takikawa, H. G. Krishnamurty, S. K. Kar, Phytochemistry, 26,
1811−1816 (1987).
8) Y. Asakawa, M. Toyota, H. Bischler, O. E. Campbell, S. Hattori, J. Hattori Bot. Lab., 57,
383−389 (1984).
9) T. Hashimoto, M. Tori, Y. Asakawa, Y. Fukuyama, Tetrahedron Lett., 28, 6295−6298(1987).
10) U. Martini, J. Zapp, H. Becker, Phytochemistry, 47, 89−96 (1998).
11) J. Qu, C. Xie, H. Guo, W. Yu, H. Lou, Phytochemistry, 68, 1767–1774 (2007).
12) M. Toyota, T. Yoshida, Y. Kan, S. Takaoka, Y. Asakawa, Tetrahedron Lett., 37,4745−4748 (1996).
13) T. Hashimoto, T. Yoshida, Y. Kan, S. Takaoka, M. Tori, Y. Asakawa, Tetrahedron Lett.,
35, 909−910 (1994).
14) Y. Asakawa, Rev. Latinoam. Quim., 14, 109 (1984).
7915) +, 

, 55, 152−158 (1997).

16) N. Tamehiro, Y. Sato, T. Suzuki, T. Hashimoto, Y. Asakawa, S. Yokohama, T. Kawanishi,
Y. Ohno, K. Inoue, T. Nagano, T. Nishimaki−Mogami, FEBS Lett., 57, 5299−5304(2005).
17) D. C. Harrowven, S. L. Kostiuk, Nat. Prod. Rep., 29, 223−242 (2012).
18) M. Iyoda, M. Sakaitani, H. Otsuka, M. Oda, Tetrahedron Lett., 26, 4777–4780 (1985).
19) M. Kodama, Y. Shiobara, H. Sumitomo, K. Matsumura, M. Tsukamoto, C. Harada, J. Org.
Chem., 53, 72–77 (1988).
20) A. Speicher, J. Holz, Tetrahedron Lett., 51, 2986–2989 (2010).
21) A. Gottsegen, M. Nogradi, B. Vermes, J. Chem. Soc., Perkin Trans. 1, 315–320 (1990).
22) A. Speicher, M. Groh, M. Hennrich, A. M. Huynh, Eur. J. Org. Chem., 6760–6778 (2010).
23) Y. Fukuyama, H. Yaso, K. Nakamura, M. Kodama, Tetrahedron Lett., 40, 105−108(1999).
24) H. Takiguchi, K. Ohmori, K. Suzuki, Chem. Lett., 40, 1069−1071 (2011).
25) T. Eicher, S. Fey, W. Puhl, E. Buchel, A. Speicher, Eur. J. Org. Chem., 877–888 (1998).
26) A. Speicher, J. Kolz, R. P. Sambanje, Synthesis, 17, 2503–2512 (2002).
27) Y. Fukuyama, H. Yaso, T. Mori, H. Takahashi, H. Minami, M. Kodama, Heterocycles, 54,
259−273 (2001).
28) H. Hioki, N. Shima, K. Kawaguchi, K. Harada, M. Kubo, T. Esumi, T.
Nishimaki−Mogami, J. Sawada, T. Hashimoto, Y. Asakawa, Y. Fukuyama, Bioorg. Med.
Chem. Lett., 19, 738–741 (2009).
29) T. Esumi, M. Wada, E. Mizushima, N. Sato, M. Kodama, Y. Asakawa, Y. Fukuyama,
Tetrahedron Lett., 45, 6941−6945 (1999).
30) ', , 56, 119−138 (2010).

31) a) D. E. Ames, A. Opalko, Synthesis, 234−235 (1983).
b) L. C. Campeau, M. Parisien, A. Jean, K. Fagnou, J. Am. Chem. Soc., 128, 581−590(2006).
c) H. Xu, L. L. Fan, Chem. Pharm. Bull., 56, 1496−1498 (2008).
d) Z. Liu, R. C. Larock, Tetrahedron, 63, 347−355 (2007).
e) Z. Liu, R. C. Larock, Org. Lett., 6, 3739−3739 (2004).
f) C. Wang, I. Piel, F. Glorius, J. Am. Chem. Soc., 131, 4194−4195 (2009).
g) A. Shiotani, H. Itatani, Angew. Chem. Int. Ed., 13, 471−472 (1974).
h) D. Hellwinkel, T. Kistenmacher, Liebigs Ann. Chem., 945−949 (1989).
i) B. Liegault, D. Lee, M. P. Huestis, D. R. Stuart, K. Fagnou, J. Org. Chem., 73, 5022−
5028 (2008).
32) a) K. Kawaguchi, K. Nakano, K. Nozaki, J. Org. Chem., 72, 5119−5128 (2007).
80b) J. Liu, A. E. Fitzgerald, N. S. Mani, J. Org. Chem., 73, 2951−2954 (2008).
33) G. Pan, Y. Ma, K. Yang, X. Zhao, H. Yang, Q. Yao, K. Lu, T. Zho, P. Yu. Tetrahedron
Lett., 56, 4472−4475 (2015).
34) A. J. Arbuzov, J. Russ. Phys. Chem. Soc., 38, 687−688 (1906).
35) D. N. Kursanov, Z. N. Parnes, G. I. Bassova, N. M. Loim, V. I. Zdanovich, Tetrahedron,23, 2235−2242 (1967).
36) a) R. Annunziata, R. Fornaisier, F. J. Montanari, J. Org. Chem., 39, 3195−3197 (1974).
b) N. J. Cusack, C. B. Reese, A. C. Risius, B. Roozpeikar, Tetrahedron, 32, 2157−2162(1976).
37) J. F. Harrod, A. Pathak, Can. J. Chem., 58, 686−693 (1980).
38) D. C. Harrowven, T. Woodcock, P. D. Howes, Angew. Chem. Int. Ed., 44, 3899−3901(2005).
39) H. Takiguchi, K. Ohmori, K. Suzuki, Angew. Chem. Int. Ed., 52, 10472−10476 (2013).
40) P. Zhao, C. M. Beaudry, Angew. Chem. Int. Ed., 53, 10500−10503 (2014).
41) 

(#!$#

*(2009).

42) P. Bovonsombat, R. Ali, C. Khan, J. Leykajarakul, K. Pla-on, S. Aphimanchindakul, N.
Pungcharoenpong, N. Timsuea, A. Arunrat, N. Punpogjareorn, Tetrahedron, 66,
6928−6935 (2010).
43) S. A. Snyder, T. C. Sherwood, A. G. Ross, Angew. Chem. Int. Ed., 49, 5146−5150 (2010).
44) K. J. Edger, S. N. Falling, J. Org. Chem., 55, 5287−5291 (1990).
45) T. Mandai, T. Matsumoto, J. Tsuji, S. Saito, Tetrahedron Lett., 34, 2513−2516 (1993).
46) E. J. Hennessy, S. L. Buchwald, J. Am. Chem. Soc., 120, 12084−12085 (2003).
47) T. Erhard, G. Ehrlich, P. Metz, Angew. Chem. Int. Ed., 50, 3892−3894 (2011).
48) Calculated by HF/6-31G* (Spartan 14).

81

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