Efficient and diversity-oriented total synthesis of Riccardin C and application to develop novel macrolactam derivatives

Article abstract of DOI:10.1016/j.tet.2011.06.018

Riccardin C (RC, 1) is a macrocyclic bis(bibenzyl) natural product exhibiting remarkable biological activity as a nuclear liver X receptors (LXRs) ligand and a lipid metabolism mediator. RC is expected to be a lead compound to develop drugs for atherosclerotic diseases, and therefore exploiting diversity-oriented synthesis of RC is a promising approach to drug discovery. In this paper, we report novel total synthesis of RC (7.4% overall yield in 16 steps) by using the intramolecular S_NAr reaction as key cyclization reaction. This is the first example of efficient macrocyclization using 3-nitro-4-fluorostilbene as an electrophile. The methodology could be applied to synthesize novel lactam analogs of RC. The diversity-oriented synthesis of RC is versatile method for the synthesis of various types of bis(bibenzyl) natural products and their derivatization.

Full text of DOI:10.1016/j.tet.2011.06.018

Tetrahedron 67 (2011) 6073e6082
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient and diversity-oriented total synthesis of Riccardin C and application
to develop novel macrolactam derivatives
*
Masazumi Iwashita, Shinya Fujii, Shigeru Ito, Tomoya Hirano, Hiroyuki Kagechika
Graduate School of Biomedical Science, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku,
Tokyo 101-0062, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 May 2011
Received in revised form 7 June 2011
Accepted 8 June 2011
Available online 1 July 2011
Riccardin C (RC, 1) is a macrocyclic bis(bibenzyl) natural product exhibiting remarkable biological activity
as a nuclear liver X receptors (LXRs) ligand and a lipid metabolism mediator. RC is expected to be a lead
compound to develop drugs for atherosclerotic diseases, and therefore exploiting diversity-oriented
synthesis of RC is a promising approach to drug discovery. In this paper, we report novel total synthe-
sis of RC (7.4% overall yield in 16 steps) by using the intramolecular SNAr reaction as key cyclization
reaction. This is the first example of efficient macrocyclization using 3-nitro-4-fluorostilbene as an
electrophile. The methodology could be applied to synthesize novel lactam analogs of RC. The diversity-
oriented synthesis of RC is versatile method for the synthesis of various types of bis(bibenzyl) natural
products and their derivatization.
Keywords:
Maclocycle
Riccardin
Bis(bibenzyl) natural product
SNAr reaction
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
Cyclic bis(bibenzyl) natural products, produced by bryophyte,
have characteristic structure and potent and diverse biological ac-
tivities.1 Riccardin C (RC, 1, Fig. 1) is a trihydroxylated cyclic bis(-
bibenzyl), isolated from the liverwort Reboulia hemisphaerica,2 and
was reported to act as a ligand for liver X receptors (LXRs).3 LXR is
a ligand-inducible transcription factor, classified in nuclear re-
ceptor superfamily, and modulates expression of ATP-binding cas-
sette transporter (ABC) A1 and ABCG1 and cellular cholesterol
efflux in THP-1 cells. Thus, LXR agonists could be potentially ef-
fective for atherosclerotic diseases, such as hyperlipidemia and
diabetes.4 Among various LXR ligands so far known, RC has unique
biological activity. There are two LXR subtypes (
RC acted selectively as LXR agonist, while RC suppressed the
function of LXR as the antagonist. Therefore, RC is a lead com-
a and b forms), and
a
b
pound for the development of novel LXR ligands as not only drug
candidates for the atherosclerotic diseases but also chemical tools
to investigate the physiological functions of each LXR subtype.
Cyclic bis(bibenzyl)s have been also attractive synthetic targets
because of their unique structure and intrinsic difficulties of mac-
rocyclization. Thus, several total syntheses of bis(bibenzyl)s have
been reported to date.1,5 Four total syntheses of RC have been
Fig. 1. Structures of Riccardin C (1), and related natural and synthetic derivatives.
using sodium metal in the macrocyclization step.6 Eicher and
Speicher adopted intramolecular Wittig construction of the ethyl-
ene linker between two phenolic parts (A and B rings of RC in
Scheme 1) in satisfactory yield,7 and recently Hashimoto also uti-
lized Wittig reaction for synthesis of some RC derivatives.8 Har-
rowven utilized McMurry coupling for the cyclization.9 Recently,
Fukuyama disclosed the novel total synthesis of RC utilizing
ꢀ
ꢀ
reported previously. Nogradi employed Wurtz coupling reaction
* Corresponding author. Tel.: þ81 3 5280 8032; fax: þ81 3 5280 8127; e-mail
address: kage.omc@tmd.ac.jp (H. Kagechika).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.018

6074
M. Iwashita et al. / Tetrahedron 67 (2011) 6073e6082
SuzukieMiyaura coupling for the construction of the macrocycle.10
These synthetic methodologies are useful to synthesize RC itself,
while these are inconvenient for development of RC analogs be-
cause of low substrate generality and applicability of the key
macrocyclization step. In order to obtain a variety of macrocyclic
analogs of RC, development of more concise and diversity-oriented
synthetic route of RC is desirable. Herein, the novel and diversity-
oriented total synthesis of RC and its application to the de-
velopment of macrolactam analogs 2 and 3 are described.
acetogenins.12 The comparatively mild conditions of SNAr reaction
are desirable to synthesize not only target compound but also its
derivatives bearing various functionalities. Thus, we chose SNAr
coupling reaction in the critical cyclization step for synthesis of RC.
In preparation of cyclization precursor 4, two ethylene linkers are
constructed by Wittig reactions, and intermolecular Suzu-
kieMiyaura cross coupling was utilized in formation of B and C
biphenyl moiety.
2.2. Total synthesis of RC
Syntheses of the B and C biphenyl fragment 5 and the D ring
fragment 7 were summarized in Scheme 2. The B ring fragment 8
was prepared from 5-methyl-2-nitroanisole (10). Reduction of nitro
group by Fe in acidic conditions, followed by Sandmeyer iodination,
gave iodide 12 in 65% (two steps). Introduction of pinacolborane
moiety by MiyauraeIshiyama protocol afforded 8 in 83%.13 Boro-
nate 8 was coupled with commercially available C ring fragment 9
under SuzukieMiyaura coupling conditions to afford biphenyl 13 in
76%.14 Bromination at the benzyl position of 13 gave 14 that was
reacted with triphenylphosphine gave phosphonium salt 5 in 68%
(two steps). The D ring fragment 7 was prepared from benzyl al-
cohol 15. Bromination of 15 using PBr3 gave bromide 16 (82%),
followed by the reaction with triphenylphosphine, gave phospho-
nium salt 7 in 78%.15
Scheme 1. Retrosynthetic analysis of RC.
Then, the compound 4 with a bis(bibenzyl) backbone, a pre-
cursor of macrocyclization, was constructed as shown in Scheme 3.
The A ring fragment 616 was reacted with phosphonium salt 5 in
Wittig reaction conditions using potassium carbonate as a base in
the presence of 18-crown-6 to afford E-stilbene 17 (55%) and
Z-stilbene 18 (45%).17 The stereochemistry of these products was
determined by 1H NMR. The coupling constant of vinyl protons of
17 was 16.3 Hz, and this characteristic coupling constant indicated
E-configuration. The mixture of olefins 17 and 18 were hydroge-
nated with Pd(OH)2 in DMF gave bibenzyl 19 in quantitative yield.
Reduction of ester group of 19, and the following oxidation gave
aldehyde 21 in 94% (two steps). Wittig reaction of 21 with D ring
fragment 7 using KHMDS as a base in THF gave Z-stilbene 22 ex-
clusively. The Wittig reaction conditions using semi-stabilized ylide
generally resulted in the mixture of E/Z isomers with the ratio of
near 1:1. The selective formation of Z isomer was preferred when
the aldehyde has an aromatic substitution at the ortho position.18
In the macrocyclization, there should be some difference in re-
activity between compound 22 with the Z-alkene linker and 23
with a more flexible alkyl linker. In order to optimize the cyclization
conditions for flexible precursor 23, compound 22 was tried to be
hydrogenated. Double bonds of stilbene or cinnamate bearing
2. Results and discussion
2.1. Retrosynthetic analysis
RC consists of four benzene rings (AeD rings, Scheme 1). The key
step of our synthetic plan is the macrocycle construction at the
diphenylether structure of A and D rings. Ullmann coupling re-
actions, Buchwald’s palladium-catalyzed synthesis, and their vari-
ations, are popular synthetic methods of diphenylether scaffold,11
while these methods generally need harsh conditions, such as
high temperature in the presence of strong bases and metals, which
sometimes troubles in purification. Considering the precedent re-
sults and the highly rigid structure of RC, use of strong base or
catalyst, or elevation of reaction temperature is expected to result
in unsatisfactory outcome. Classical SNAr coupling of phenol with
electron-deficient haloaryl moiety is also well utilized to construct
diaryl ether, because of its mild and simple reaction conditions.
Therefore, it was applied to synthesis of natural products contain-
ing diaryl ether macrocycle, such as peptide antibiotics and
Scheme 2. Syntheses of B and C ring fragment 5 and D ring fragment 7.

M. Iwashita et al. / Tetrahedron 67 (2011) 6073e6082
6075
Scheme 3. Synthesis of cyclization precursor 4.
fluoronitrophenyl moiety can be hydrogenated catalytically to al-
kanes by Wilkinson’s catalyst.19 However, reduction of 22 under the
reported conditions did not occur. Therefore, we optimized the
condition of macrocyclization using 4, obtained by acidic treatment
of 22, as the cyclization precursor.
18-crown-6 at 40 ꢀC was selected as the cyclization conditions of 4.
It is noteworthy that the result was the first successful SNAr mac-
rocyclization of electrophilic styrylbenzene.
Based on the cyclization results employing the Z-stilbene 4 as
a substrate, we examined the applicability of the conditions to E-
stilbene substrate. The cyclization precursor with E-stilbene
structure was prepared by JuliaeKocienski coupling reaction.20
Mitsunobu reaction of thiol 25 and 3-fluoro-4-nitrobenzylalcohol
(15) gave sulfide 26 in 97%, which was subsequently oxidized by
m-CPBA to afford sulfone 27 in 91%. JuliaeKocienski coupling of 27
with aldehyde 21 gave E-stilbene 28, predominantly with a small
amount of Z-isomer 22 as byproduct, in 89% (E/Z ratio¼16:1). The
deprotection of MOM group gave the cyclization precursor 29 with
coexistence of a trace amount of 4. The mixture of 29 and 4 (ratio of
16:1) was subjected to the optimized cyclization conditions (Table
1, entry 8), but the desirable cyclized product was obtained only
in trace amount as a mixture of 1:1 E/Z isomer. The results sug-
gested that Z-configuration of the precursor was superior to
E-isomer in the macrocyclization of bis(bibenzyl) derivatives by
SNAr reaction (Scheme 4).
The results of investigation on the optimal cyclization condi-
tions are summarized in Table 1. In previously reported intra-
molecular SNAr synthesis of ortho-substituted diphenylether,
cyclization proceeded successfully in the presence of weak bases,
such as cesium fluoride or potassium carbonate at room tempera-
ture.11,12 In the case of cyclization of 4, the reactions using cesium
fluoride or potassium carbonate were examined at ambient tem-
perature, but the reaction did not proceed (entry 1 and 2). Cycli-
zation reaction of 4 with stronger base, such as potassium tert-
butoxide or sodium hydride did occur, but the yield of desired
macrocyclic compound 24 was not sufficient (entry 3e5). Alter-
natively, the reaction using potassium carbonate at higher tem-
perature (entry 6) or in the presence of 18-crown-6 (entry 7 and 8)
improved the yield of 24. In the result of optimization, the reaction
using potassium carbonate in the presence of 0.2 equiv of
Table 1
Cyclization of 4
Conditions
Entry
Base
Additive
Solventa
Temp
Yield
1
2
3
4
5
6
7
8
CsF
d
DMF
DMF
DMF
DMF
CH3CN
DMF
DMF
DMF
rt
rt
0
0
0
70 ꢀC
45 ꢀC
40 ꢀC
N.R.b
N.R.b
14%
26%
37%
45%
39%
60%
K2CO3
t-BuOK
t-BuOK
NaH
K2CO3
K2CO3
K2CO3
d
d
ꢀC to rt
d
ꢀC to rt
ꢀC to rt
d
d
18-crown-6 (0.1 equiv)
18-crown-6 (0.2 equiv)
a
Concentration of 4 was 0.01 M in each condition.
No reaction.
b

6076
M. Iwashita et al. / Tetrahedron 67 (2011) 6073e6082
Scheme 4. Preparation and cyclization of E-stilbene 29.
Macrocyclic Z-stilbene 24 obtained from 4 was subjected to
and conversion into phosphonium salt gave 36 in 57% (two steps).
Wittig reaction of 36 with 6 by using potassium carbonate as a base
in the presence of 18-crown-6 gave E-stilbene 37 (44%) and Z-iso-
mer 38 (39%). Hydrogenation of the nitro group of 37 gave amine 39
in 85%. Amide condensation of 39 with 4-fluoro-3-nitrobenzoyl
chloride, followed by removal of MOM group, gave cyclization
precursor 41. The critical macrocyclization based on the optimized
conditions (Table 1, entry 8) gave the cyclized compound 42 in 74%.
Catalytic hydrogenation of 42 and deamination gave 44, which was
finally demethylated using boron tribromide to afford tetraaryl
macrolactam 2. N-Methylation of 44 and demethylation of three O-
methoxy groups gave N-methylamide derivative 3. Thus, the mac-
rolactams could be obtained easily by using SNAr reaction as key
macrocyclization reaction.
catalytic hydrogenation gave amine 31 in 92%, and subsequent
deamination via diazonium salt gave trimethyl ether of RC (32) in
83%. Finally, removal of three O-methyl groups of 32 with boron
tribromide afforded RC (1) in 78%. Here novel total synthesis of RC
was accomplished in 7.4% overall yield in 16 steps. Synthesized RC
was identical to the authentic sample in 1H and 13C NMR spectra
and HRMS (Scheme 5).
2.4. Discussions
SNAr diary ether synthesis was useful methodology to prepare
RC and its analogs. In the course of total synthesis of RC, we ex-
amined SNAr macrocyclization of three precursors, that is, Z-stil-
bene 4, E-stilbene 29 and benzanilide-type substrate 41, in which
the conformational and electronic structures of bibenzyl moiety are
different each other. As a result, Z-stilbene 4 and benzanilide 41
underwent SNAr cyclization with sufficient yield, while E-stilbene
29 did not. It is interesting that benzanilide 41 underwent SNAr
macrocyclization efficiently although the predominant conforma-
tion of benzanilide part is trans, like E-stilbene 29. The differences
in reactivity could arise from three reasons. One is flexibility of the
amide structure of 41. The results of stilbenes suggested that con-
formation of the substrate with Z-olefinic bond is suitable for the
macrocyclization of the RC type cyclic bis(bibenzyl) scaffold. Al-
though the conformation based on E structure is the predominant
conformation for both 29 and 41, the rotation barrier of amide bond
is lower than that of olefinic bond. Therefore, the anilide 41 could
react at the reaction conditions affording the desired macrocycle 42
in sufficient yield. The second is electronic effect. The electron-
withdrawing carbonyl function of the amide group increased the
reactivity of the carbon atom attached to the fluorine atom toward
Scheme 5. Completion of total synthesis of RC (1).
2.3. Synthesis of novel macrolactam analogs of RC
We investigated an applicability of our synthetic methodology
to develop macrocyclic analogs of RC. As novel macrocyclic analogs
of RC, we designed macrolactam 2 and 3 (Fig. 1). The ethylene
linking group of 1 was replaced with more rigid and planar amide
group, which may affect the three-dimensional structure and
electronic distribution of the macrocycle, and therefore those
compounds should contribute to the understanding of structur-
eeactivity relationships of bioactivity of RC.
In our preliminary investigation, formation of tetraaryl macro-
lactam, such as 2 and 3 by amide condensation was extremely
difficult. On the bases of our results, SNAr macrocyclization after
construction of amide moiety might be superior method than
macrolactamization. Therefore, we examined the synthesis of novel
macrolactone analog of RC via SNAr macrocyclization.
the SNAr cyclization. In E-stilbene 29, the p-electrons of the phenyl
ring will delocalize with the olefinic bond, which would decrease
the reactivity. The effect will be less in Z-stilbene 4, because of the
twisted conformation between phenyl ring and Z-olefinic bond. In
addition, thermodynamic stability of cyclized compounds is an-
other reason. Macrocycle 30 with E-olefin substructure is thought
Synthesis of the designed macrolactams 2 and 3 was shown in
Scheme 6. 4-Iodo-3-nitroanisole 3321 corresponding to the part of C
ring was coupled with boronate 8 under SuzukieMiyaura condi-
tions to afford biphenyl 34 in 81%. Subsequent bromination of 34

M. Iwashita et al. / Tetrahedron 67 (2011) 6073e6082
6077
Scheme 6. Synthesis of novel macrolactam 2 and 3.
to have distortion of skeletal bonds, and therefore formation of 30
would be energetically disadvantageous.
4.1.1. 4-Iodo-3-methoxytoluene (12). Iron (5.35 g, 95.7 mmol) was
added to solution of 2-nitro-5-methylanisole (10, 4.00 g,
a
23.9 mmol) in ethanol (60 ml) and 6 M aqueous hydrochloric acid
(30 ml), and the mixture was heated at reflux for 2 h. The reaction
mixture was diluted with ethyl acetate and filtrated through Celite.
Evaporation of the filtrate afforded crude 11. NaNO2 (2.11 g,
30.6 mmol) was added to a solution of crude 11 (2.80 g, 20.4 mmol)
in THF (80 ml) and 4 M aqueous hydrochloric acid (40 ml) at 0 ꢀC.
After 30 min, potassium iodide (4.80 g, 30.6 mmol) was added, and
the mixture was heated at reflux for 3 h. The reaction mixture was
diluted with ethyl acetate and water. The organic layer was washed
with saturated sodium thiosulfate and brine, dried with sodium
sulfate, and evaporated. Purification by silica gel column chroma-
tography (n-hexane/ether 100:1 to 98:2) gave 12 (pale yellow oil,
3.77 g, 15.2 mmol, 65% for two steps). 1H NMR (500 MHz, CDCl3)
3. Conclusion
We established concise and efficient synthesis of RC in 7.4%
overall yield in 16 steps. The critical ring closure was succeeded in
60% yield by intramolecular SNAr reaction, and the requisite syn-
thetic fragments were readily available. The novel SNAr macro-
cyclization enables development of diverse RC analogs bearing
various functional groups on aromatic rings and various linkers
between aromatic rings. RC have unique biological activity as
LXRa-specific agonist, while there is only a few studies on the
structureeactivity relationship, and most of them are simple
chemical transformation of natural products. The concise and
diversity-oriented synthesis of RC described here would provide
the useful synthetic methodology in the medicinal chemistry and
chemical biology research of RC and the related bis(bibenzyl)-type
macrocycles.
d
7.60 (d, 1H, J¼7.9 Hz), 6.63 (d, 1H, J¼1.2 Hz), 6.53 (dd, 1H, J¼7.9,
1.2 Hz), 3.84 (s, 3H), 2.31 (s, 3H); 13C NMR (125 MHz, CDCl3)
d
157.84, 139.86, 138.96, 123.36, 112.07, 81.78, 56.18, 21.42; HRMS
(FABþ) m/z 248.9780 [(MþH)þ: calcd for C8H10OI, 248.9776].
4.1.2. (2-Methoxy-4-methylphenyl)boronic acid pinacol ester (8).
Compound 12 (7.44 g, 30.0 mmol) in DMSO (20 ml) was added to
a suspension of bis(pinacolate)diboron (8.38 g, 33.0 mmol) and pre-
dried potassium acetate (8.84 g, 90.0 mmol) and PdCl2(dppf)$CH2Cl2
(735 mg, 0.900 mmol) in DMSO (80 ml) under Ar atmosphere, and
the mixture was stirred for 5 h at 80 ꢀC. The reaction mixture was
diluted with ethyl acetate and filtered through Celite. The organic
layer was washed with water and brine, dried with sodium sulfate,
and evaporated. Purification by silica gel column chromatography
(n-hexane/ethyl acetate 10:1) gave 8 (colorless solids, 6.19 g,
4. Experimental section
4.1. General methods
All reagents were purchased from SigmaeAldrich Chemical Co.,
Tokyo Kasei Kogyo Co, Wako Pure Chemical Industries, Kanto
Kagaku Co., INC. Silica gel for column chromatography was pur-
chased from Kanto Kagaku Co., INC. Gel permeation chromatogra-
phy was conducted with LG-9201 (Japan Analytical Industry Co.,
Ltd., eluent: CHCl3). 1H and 13C NMR spectra were recorded on
25.0 mmol, 83%). Mp 59.5e60.0 ꢀC; 1H NMR (500 MHz, CDCl3)
(d,1H, J¼7.5 Hz), 6.74 (d,1H, J¼7.3 Hz), 6.65 (s, 1H), 3.80 (s, 3H), 2.33
d 7.55
(s, 3H), 1.32 (s, 12H); 13C NMR (125 MHz, CDCl3)
d 164.39, 142.98,
a BRUKER AVANCE 500 spectrometer. Chemical shifts for 1H and 13
C
136.81,120.99,111.44, 83.20, 55.74, 24.98, 24.77, 21.90; HRMS (FABþ)
NMR are reported as parts per million (ppm) relative to chloroform
(7.24 ppm for 1H NMR, 77.00 ppm for 13C NMR). Mass Spectral data
was collected on Bruker Daltonics microTOF-2focus or JEOL
AX505H in the positive and negative ion modes. Elemental analyses
were carried out by Yanaco MT-6 CHN CORDER spectrometer.
m/z 248.1697 [(M)þ: calcd for C14H22O3B, 248.1584].
4.1.3. Methyl 20,4-dimethoxy-40-methylbiphenyl-2-carboxylate
(13). Tripotassium phosphate (9.55 g, 45.0 mmol) and

6078
M. Iwashita et al. / Tetrahedron 67 (2011) 6073e6082
PdCl2(dppf)$CH2Cl2 (612 mg, 0.750 mmol) was added to the solu-
tion of compound 8 (3.97 g, 16.0 mmol) and methyl 2-bromo-5-
methoxybenzoate (9) (3.68 g, 15.0 mmol) in DMF (75 ml) and wa-
ter (1.5 ml) under argon atmosphere, and the mixture was stirred
for 3 h at 80 ꢀC. The reaction mixture was filtered through Celite,
and diluted with water, and extracted with CH2Cl2. The organic
layer was washed with water and brine, dried with sodium sulfate,
and evaporated. Purification by silica gel column chromatography
(n-hexane/ethyl acetate 10:1) gave 13 (colorless oil, 3.25 g,
J¼12.5Hz),128.25,125.59 (d, J¼4.2 Hz),119.25 (d, J¼18.6 Hz), 117.03 (d,
3C, J¼85.9 Hz), 26.96 (d, J¼45.3 Hz); HRMS (ESIþ) m/z 416.1211
[(MþH)þ: calcd for C25H20FNO2P, 416.1210].
4.1.7. Methyl
20,4-dimethoxy-40-[4-methoxy-3-(methoxymethoxy)
styryl]biphenyl-2-carboxylate [17 (E isomer) and 18 (Z isomer)].
Potassium carbonate (464 mg, 3.35 mmol) and 18-crown-6 (59.2 mg,
0.224 mmol) was added to a solution of 5 (1.40 g, 2.24 mmol) and 6
(526 mg, 2.68 mmol) in methylene chloride (30 ml), and the mixture
was heated at reflux for 2 days. The reaction mixturewas evaporated
and dissolved in THF (30 ml) and MeOH (30 ml), and NaBH4
(60.0 mg) was added the mixture at 0 ꢀC, and the mixture was stirred
for 2 h at room temperature. The reaction mixture was poured into
2 M aqueous hydrochloric acid at 0 ꢀC and diluted with ethyl acetate.
The organic layer was washed with 2 M aqueous hydrochloric acid
and brine, dried with sodium sulfate, and evaporated. Purification by
silica gel column chromatography (n-hexane/ethyl acetate 3:1 to
7:3) gave 17 (colorless oil, 605 mg,1.30 mmol, 55%) and 18 (colorless
oil, 491 mg, 1.06 mmol, 45%). Compound 17; 1H NMR (500 MHz,
11.4 mmol, 76%). 1H NMR (500 MHz, CDCl3)
d
7.37 (d, 1H, J¼2.8 Hz),
7.22 (d, 1H, J¼8.5 Hz), 7.10 (d, 1H, J¼7.5 Hz), 7.06 (dd, 1H, J¼8.5,
2.8 Hz), 6.82 (dd, 1H, J¼7.6, 0.6 Hz), 6.69 (s, 1H), 3.85 (s, 3H), 3.69 (s,
3H), 3.65 (s, 3H), 2.38 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 168.51,
158.33, 155.94, 138.46, 132.52, 132.46, 131.09, 129.70, 127.33, 121.33,
117.60, 114.15, 111.13, 55.45, 55.13, 51.69, 21.62; HRMS (ESIþ) m/z
309.1103 [(MþNa)þ: calcd for C17H18NaO4, 309.1097].
4.1.4. [(2,40-Dimethoxy-20-methoxycarbonylbiphenyl-4-yl)methyl]
triphenylphosphonium bromide (5). N-Bromosuccinimide (NBS:
200 mg, 1.12 mmol) was added to a solution of 13 (388 mg,
1.36 mmol) and 2,20-azobis(isobutyronitrile) (11.2 mg, 0.068 mmol)
in CCl4 (20 ml), and the mixture was heated at reflux. After 1 h,
additional NBS (41.6 mg, 0.234 mmol) was added and refluxed for
1 h, and NBS (20.0 mg, 0.112 mmol) was further added and refluxed
for another 1 h. The reaction mixture was filtered through Celite,
and the filtrate was evaporated. Purification by silica gel column
chromatography (n-hexane/ethyl acetate 10:1) gave bromide 14
(colorless oil, 442 mg). A solution of compound 14 (442 mg) and
triphenylphosphine (317 mg, 1.21 mmol) in acetonitrile (15 ml) was
heated at reflux for 14 h. The resulting white precipitates were
filtrated, washed with ether, and dried in vacuo to afford 5 (color-
less solids, 578.0 mg, 0.921 mmol, 68% for two steps). Mp
CDCl3)
d
7.38 (d, 1H, J¼2.8 Hz), 7.36 (d, 1H, J¼2.1 Hz), 7.25 (d, 1H,
J¼8.7 Hz), 7.19 (d, 1H, J¼7.7 Hz), 7.14 (dd, 1H, J¼7.7, 1.3 Hz), 7.13 (dd,
1H, J¼8.4, 2.1 Hz), 7.06 (dd,1H, J¼8.5, 2.8 Hz), 7.04 (d,1H, J¼16.3 Hz),
7.01e6.98 (m, 2H), 6.97 (d,1H, J¼16.3 Hz), 6.88 (d,1H, J¼8.4 Hz), 5.28
(s, 2H), 3.89 (s, 3H), 3.85 (s, 3H), 3.76 (s, 3H), 3.64 (s, 3H), 3.55 (s, 3H);
13C NMR (125 MHz, CDCl3)
d 168.57, 158.51, 156.34, 149.57, 146.76,
137.99, 132.56, 132.43, 130.72, 130.63, 130.11, 129.56, 128.14, 127.02,
121.16, 119.19, 117.67, 114.23, 114.06, 111.81, 107.73, 95.57, 56.26,
55.99, 55.49, 55.23, 51.74; HRMS (FABþ) m/z 464.1841 [(M)þ: calcd
for C27H28O7, 464.1835]. Compound 18; 1H NMR (500 MHz, CDCl3)
d
7.36 (d, 1H, J¼2.8 Hz), 7.22 (d, 1H, J¼8.5 Hz), 7.12 (d, 1H, J¼2.1 Hz),
7.10 (d,1H, J¼7.7 Hz), 7.05 (dd,1H, J¼8.5, 2.8 Hz), 6.96e6.92 (m, 2H),
6.78 (d,1H, J¼1.4 Hz), 6.76 (d,1H, J¼8.4 Hz), 6.52 (s, 2H), 5.08 (s, 2H),
3.84 (s, 3H), 3.83 (s, 3H), 3.64 (s, 3H), 3.51 (s, 3H), 3.40 (s, 3H); 13C
264.5e265.0 ꢀC; 1H NMR (500 MHz, DMSO-d6)
d 7.93e7.88 (m, 3H),
7.78e7.71(m, 6H), 7.71e7.64 (m, 6H), 7.32 (d, 1H, J¼2.7 Hz), 7.16 (d,
1H, J¼8.5 Hz), 7.11 (dd,1H, J¼8.5, 2.8 Hz), 7.04 (dd,1H, J¼7.7, 0.7 Hz),
6.69 (m, 1H), 6.47 (m, 1H), 4.93 (d, 2H, J¼14.7 Hz), 3.83 (s, 3H), 3.65
NMR (125 MHz, CDCl3) d 168.52, 158.47, 155.77, 149.10, 146.00,
137.69, 132.59, 132.39, 130.74, 130.20, 129.72 (2C), 129.16, 129.08,
123.41, 121.50, 117.63, 117.47, 114.17, 111.40, 110.52, 95.55, 56.08,
55.87, 55.47, 54.97, 51.66; HRMS (FABþ) m/z 464.1819 [(M)þ: calcd for
C27H28O7, 464.1835].
(s, 3H), 3.27 (s, 3H); 13C NMR (125 MHz, DMSO-d6)
d 169.64, 160.31,
157.84, 136.45 (d, J¼2.8 Hz), 135.61 (d, J¼9.5 Hz), 133.81, 133.42,
132.48, 131.40 (d, J¼12.5 Hz), 128.67 (d, J¼9.1 Hz), 124.55 (d,
J¼6.0 Hz), 119.53, 118.84, 118.22, 115.64, 114.25 (d, J¼4.8 Hz), 56.04,
55.58, 52.39, 31.20 (d, J¼47.8 Hz); HRMS (ESIþ) m/z 547.2039
[(MþH)þ: calcd for C35H32O4P, 547.2038].
4.1.8. Methyl
20,4-dimethoxy-40-[4-methoxy-3-(methoxymethoxy)
phenethyl]biphenyl-2-carboxylate (19). Pd(OH)2 on carbon (10%,
2.0 mg) was added to a solution of 17 and 18 (10.5 mg, 0.226 mmol)
in DMF (1.5 ml). The reaction mixture was stirred for 20 h under
hydrogen atmosphere at room temperature, and filtered through
Celite. The filtrate was poured into ethyl acetate and water. The
organic layer was washed with water and brine, dried with sodium
sulfate, and evaporated. Purification by silica gel column chroma-
tography (n-hexane/ethyl acetate 2:1) gave 19 (colorless oil,
4.1.5. 4-Fluoro-3-nitrobenzyl bromide (16). A solution of 4-fluoro-
3-nitrobenzylalcohol (3.04 g, 17.8 mmol) in ether (20 ml) was
added dropwise to a solution of phosphorus tribromide (1.92 g,
7.11 mmol) in ether (80 ml) at 0 ꢀC, and the mixture was stirred for
2 h at ambient temperature. The reaction mixture was washed with
saturated aqueous sodium bicarbonate and brine, dried with so-
dium sulfate, and evaporated to afford 16 (pale yellow solids, 3.41 g,
14.6 mmol, 82%). Mp 55.5e56.0 ꢀC; 1H NMR (500 MHz, CDCl3)
10.4 mg, 0.223 mmol, 99%). 1H NMR (500 MHz, CDCl3)
d 7.36 (d, 1H,
J¼2.7 Hz), 7.23 (d, 1H, J¼8.5 Hz), 7.12 (d, 1H, J¼7.6 Hz), 7.06 (dd, 1H,
J¼8.5, 2.8 Hz), 7.01 (br s), 6.84 (dd, 1H, J¼7.6, 1.5 Hz), 6.81 (m, 2H),
6.65 (d, 1H, J¼1.3 Hz), 5.20 (s, 2H), 3.85 (s, 6H), 3.66 (s, 3H), 3.63 (s,
3H), 3.51 (s, 3H), 2.94e2.85 (m, 4H); 13C NMR (125 MHz, CDCl3)
d
8.08 (dd, 1H, J¼6.9, 2.3 Hz), 7.66 (ddd, 1H, J¼8.6, 4.1, 2.4 Hz), 7.27
(dd, 1H, J¼10.4, 8.6 Hz), 4.47 (s, 2H); 13C NMR (125 MHz, CDCl3)
d
155.09 (d, J¼266.7 Hz), 135.98 (d, J¼8.9 Hz), 134.98 (d, J¼4.3 Hz),
d 168.55, 158.35, 155.96, 148.03, 146.33, 142.33, 134.57, 132.50,
126.47, 126.46 (d, J¼2.2 Hz), 119.00 (d, J¼22.1 Hz), 30.22; HRMS
130.99, 129.76, 127.82, 122.14, 120.67, 117.61, 116.92, 114.13, 111.75,
110.51, 95.59, 56.17, 55.97, 55.45, 51.66, 38.15, 37.12. HRMS (ESIþ)
m/z 489.1892 [(MþNa)þ: calcd for C27H30NaO7, 489.1884].
(EIþ) m/z 232.9494 [(MþH)þ: calcd for C7H5NO2BrF, 232.9488].
4.1.6. 4-Fluoro-3-nitrobenzyltriphenylphosphonium bromide (7). A
solution of compound 16 (3.41 g,14.6 mmol) and triphenylphosphine
(3.82 g, 14.6 mmol) in acetonitrile (40 ml) was heated at reflux for 1
day. The resulting white precipitates were collected and washed with
ether, and dried in vacuo to afford 7 (colorlesssolids, 5.67 g,11.4 mmol,
4.1.9. 2-Hydroxymethyl-20,4-dimethoxy-40-[4-methoxy-3-(methox-
ymethoxy)phenethyl]biphenyl (20). Diisobutylaluminium hydride
(1.02 M in n-hexane, 3.68 ml, 3.75 mmol) was added to a solution of
19 (700 mg, 1.50 mmol) in THF (20 ml) at ꢁ78 ꢀC under Ar atmo-
sphere, and the mixture was stirred for 2 h at ambient temperature.
The reaction mixture was poured into 2 M aqueous hydrochloric
acid at 0 ꢀC, and diluted with ethyl acetate. The organic layer was
washed with 2 M aqueous hydrochloric acid and brine, dried with
78%). Mp >300 ꢀC; 1H NMR (500 MHz, DMSO-d6)
d 7.95e7.89 (m, 3H),
7.79e7.68 (m, 13H), 7.55e7.46 (m, 2H), 5.43 (d, J¼15.7 Hz); 13C NMR
(125 MHz, DMSO-d6)
136.29,135.26 (d, 3C, J¼2.6 Hz),134.08 (d, 6C, J¼10.0Hz),130.20(d, 6C,
d
154.54 (d, J¼261.3 Hz), 138.52 (d, J¼6.9 Hz),

M. Iwashita et al. / Tetrahedron 67 (2011) 6073e6082
6079
sodium sulfate, and evaporated. Purification by silica gel column
chromatography (n-hexane/ethyl acetate 2:1 to 1:1) gave 20 (col-
orless oil, 671 mg, 1.53 mmol, quant.). 1H NMR (500 MHz, CDCl3)
with water and brine, dried with sodium sulfate, and evaporated.
Purification by silica gel column chromatography (n-hexane/ethyl
acetate 4:1) gave 4 (orange oil, 58.7 mg, 0.111 mmol, 98%). 1H NMR
d
7.10 (d, 1H, J¼7.5 Hz), 7.09 (d, 1H, J¼3.0 Hz), 7.03 (d, 1H, J¼7.6 Hz),
(500 MHz, CDCl3)
d
7.75 (dd, 1H, J¼7.1, 2.2 Hz), 7.39 (ddd, 1H, J¼8.4,
6.98 (d, 1H, J¼1.3 Hz), 6.88 (dd, 1H, J¼8.3, 2.7 Hz), 6.84 (dd, 1H,
J¼7.6, 1.5 Hz), 6.83e6.79 (m, 2H), 6.73 (d, 1H, J¼1.4 Hz), 5.20 (s, 2H),
4.39 (d, 2H, J¼15.6 Hz), 3.85 (s, 3H), 3.84 (s, 3H), 3.69 (s, 3H), 3.51(s,
3H), 2.95e2.86 (m, 4H), 2.20 (t, 1H, J¼6.2 Hz); 13C NMR (125 MHz,
4.2, 1.8 Hz), 7.21 (d, 1H, J¼8.5 Hz), 7.02 (dd, 1H, J¼10.6, 8.7 Hz), 6.92
(d, 1H, J¼7.5 Hz), 6.86 (dd, 1H, J¼8.5, 2.7 Hz), 6.78 (d, 1H, J¼2.1 Hz),
6.77 (d, 1H, J¼8.2 Hz), 6.74 (dd, 1H, J¼8.6, 1.5 Hz), 6.69 (d, 1H,
J¼2.8 Hz), 6.67 (dd, 1H, J¼8.2, 2.1 Hz), 6.65 (d, 1H, J¼1.3 Hz), 6.51 (d,
1H, J¼12.0 Hz), 6.29 (d,1H, J¼12.0 Hz), 5.58 (s, 2H), 3.86 (s, 3H), 3.68
(s, 3H), 3.62 (s, 3H), 2.92e2.84 (m, 4H); 13C NMR (125 MHz, CDCl3)
CDCl3)
d 159.22, 156.40, 148.09, 146.35, 142.79, 140.77, 134.40,
131.43, 131.34, 129.69, 127.11, 122.16, 121.04, 116.94, 113.39, 113.32,
111.80, 111.45, 95.59, 63.83, 56.17, 55.98, 55.70, 55.27, 38.12, 37.17;
HRMS (ESIþ) m/z 461.1939 [(MþNa)þ: calcd for C26H30NaO6,
461.1935].
d
158.57, 156.63, 153.98 (d, J¼257.5 Hz), 145.47, 144.86, 142.76,
137.08, 136.81, 135.55 (d, J¼8.3 Hz), 135.07, 134.34 (d, J¼3.6 Hz),
133.39, 132.03, 130.84, 130.77, 127.00, 126.10, 125.78, 120.32, 119.73,
117.70 (d, J¼21.0 Hz), 114.71, 113.98, 113.43, 110.98, 110.61, 56.01,
55.25, 55.07, 38.05, 37.08; HRMS (ESIþ) m/z 552.1800 [(MþNa)þ:
calcd for C31H28FNNaO6, 552.1793].
4.1.10. 20,4-Dimethoxy-40-[4-methoxy-3-(methoxymethoxy)phe-
nethyl]biphenyl-2-aldehyde (21). Sulfur trioxide-pyridine complex
(1.46 g, 9.19 mmol) was added to a solution of 20 (671 mg,
1.53 mmol) in methylene chloride (20 ml) and DMSO (4.0 ml) and
distilled triethylaminde (2.0 ml,14.7 mmol) at 0 ꢀC, and the mixture
was stirred for 2 h at room temperature. 2 M aqueous sodium hy-
droxide was added at 0 ꢀC and, the mixture was stirred for 30 min.
The organic layer was washed with 2 M aqueous sodium hydroxide,
2 M aqueous hydrochloric acid and brine, dried with sodium sul-
fate, and evaporated. Purification by silica gel column chromatog-
raphy (n-hexane/ethyl acetate¼2:1) gave 21 (colorless oil, 614 mg,
4.1.13. (Z)-Macrocyclic ether 24 (Table 1. entry 8). Potassium car-
bonate (138 mg, 1.00 mmol) and 18-crown-6 (21.2 mg, 0.080 mmol)
was added to a solution of 4 (212 mg, 0.400 mmol) in DMF (40 ml),
and the mixture was stirred for 2 h at 40 ꢀC. The reaction mixture
was poured into a mixture of ethyl acetate and water. The organic
layer was washed with water and brine, dried with sodium sulfate,
and evaporated. Purification by silica gel column chromatography
(n-hexane/ethyl acetate 6:1) gave 24 (pale yellow oil, 116 mg,
0.242 mmol, 60%). 1H NMR (500 MHz, CDCl3): Two conformers
1.41 mmol, 94%). 1H NMR (500 MHz, CDCl3)
d 9.72 (s, 1H), 7.47 (d,
1H, J¼2.8 Hz), 7.26 (d, 1H, J¼8.5 Hz), 7.17 (dd, 1H, J¼8.4, 2.8 Hz), 7.14
(d, 1H, J¼7.5 Hz), 6.99 (d, 1H, J¼1.7 Hz), 6.87 (dd, 1H, J¼7.6, 1.5 Hz),
6.82 (d, 1H, J¼8.2 Hz), 6.79 (dd, 1H, J¼8.2, 1.8 Hz), 6.71 (d, 1H,
J¼0.8 Hz), 5.20 (s, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 3.68 (s, 3H), 3.50 (s,
were observed.
d
7.69 (d, 1H (major), J¼2.2 Hz), 7.66 (d, 1H (minor),
J¼2.2 Hz), 7.31 (br d, 1H (major), J¼8.6 Hz), 7.28 (dd, 1H (minor),
J¼8.4, 1.8 Hz), 7.23e7.19 (m, 1H), 6.97 (d, 1H, J¼7.7 Hz), 6.93e6.80
(m, 5H), 6.77 (d, 1H, J¼7.7 Hz), 6.38e6.22 (m, 3H), 5.22 (d, 1H
(major), J¼2.3 Hz), 5.14 (d, 1H (minor), J¼8.4 Hz), 3.94 (s, 3H (ma-
jor)), 3.93 (s, 3H (minor)), 3.86 (s, 3H), 3.63 (s, 3H (major)), 3.62 (s,
3H (minor)), 2.90e2.68 (m, 4H); HRMS (ESIþ) m/z 532.1738
[(MþNa)þ: calcd for C31H27NNaO6, 532.1731].
3H), 2.99e2.85 (m, 4H); 13C NMR (125 MHz, CDCl3)
d 192.64,159.04,
156.48, 148.12, 146.40, 143.78, 134.87, 134.72, 134.28, 132.51, 131.43,
124.09, 122.18, 121.21, 121.01, 116.90, 111.78, 111.02, 109.33, 95.60,
56.19, 56.00, 55.53, 55.34, 38.18, 37.14. HRMS (ESIþ) m/z 459.1789
[(MþNa)þ: calcd for C26H28NaO6, 459.1778].
4.1.14. 5-(4-Fluoro-3-nitrobenzylthio)-1-phenyltetrazole (26). Diethyl
azodicarboxylate (2.2 M in toluene, 1.82 ml, 4.00 mmol) was added
4.1.11. (Z)-2-(4-Fluoro-3-nitrostyryl)-20,4-dimethoxy-40-[4-methoxy-
3-(methoxymethoxy)phenethyl]biphenyl (22). KHMDS (0.5
M
in
to a mixture of 4-fluoro-3-nitrobenzylalcohol 15 (513 mg,
toluene, 9.20 ml, 4.60 mmol) was added to a suspension of 7
(1.90 g, 3.83 mmol) in THF (15 ml) at 0 ꢀC under argon atmo-
sphere, and the mixture was stirred for 30 min at ambient tem-
perature. A solution of 21 (614 mg, 1.32 mmol) in THF (5.0 ml) was
added to the reaction vessel at 0 ꢀC and, the mixture was stirred
for 1 day at room temperature. The reaction mixture was poured
into 2 M aqueous hydrochloric acid and ethyl acetate. The organic
layer was washed with 2 M aqueous hydrochloric acid and brine,
dried with sodium sulfate, and evaporated. Purification by silica
gel column chromatography (n-hexane/ethyl acetate 4:1 to 3:1)
gave 22 (orange oil, 619 mg, 1.08 mmol, 82%). 1H NMR (500 MHz,
3.00 mmol), 5-mercapto-1-phenyltetrazole 25 (535 mg, 3.30 mmol),
and triphenylphosphine (1.41 g, 4.00 mmol) in THF (15 ml) at 0 ꢀC
under argon atmosphere, and the mixture was stirred for 3 h at 0 ꢀC.
After evaporation, the crude product was purified by silica gel col-
umn chromatography (n-hexane/ethyl acetate 7:3) to afford 26
(963 mg, 2.91 mmol, 97%) as yellow solids. Mp 127.5e128.0 ꢀC; 1H
NMR (500 MHz, CDCl3)
d
8.14 (dd, 1H, J¼6.8, 2.3 Hz), 7.79 (ddd, 1H,
J¼8.5, 4.1, 2.4 Hz), 7.57e7.47 (m, 5H), 7.23 (dd, 1H, J¼10.5, 8.6 Hz),
4.60 (s, 2H); HRMS (FABþ) m/z 332.0627 [(MþH)þ: calcd for
C14H11FN5O2S, 332.0617].
CDCl3)
d
8.67 (s, 1H), 8.23 (dd, 1H, J¼8.6, 2.3 Hz), 8.13e8.08 (m,
4.1.15. 5-(4-Fluoro-3-nitrobenzylsulfonyl)-1-phenyltetrazole
(27). m-Chloroperbenzoic acid (77%, 672 mg, 3.00 mmol) was
added to a solution of 26 (166 mg, 0.500 mmol) in methylene
chloride (10 ml), and the mixture was stirred for 1 day at ambient
temperature. The reaction mixture was poured into saturated so-
dium thiosulfate. The organic layer was washed with brine, dried
with sodium sulfate, and evaporated. The crude product was pu-
rified by silica gel column chromatography (n-hexane/ethyl acetate
7:3) to afford 27 (165 mg, 0.454 mmol, 91%) as yellow solids. Mp
1H), 7.80 (s, 1H), 7.35 (dd, 1H, J¼10.0, 8.8 Hz), 7.20 (d, 1H,
J¼8.5 Hz), 7.14 (d, 1H, J¼8.2 Hz), 6.95e6.90 (m, 3H), 6.84e6.79 (m,
3H), 5.13 (s, 2H), 3.87 (s, 6H), 3.83 (s, 3H), 3.45 (s, 3H), 2.99e2.93
(m, 3H), 2.93e2.85 (m, 2H); 13C NMR (125 MHz, CDCl3)
d 161.46,
159.57, 157.27 (d, J¼271.0 Hz), 155.33, 148.10, 146.29, 143.94, 136.80
(d, J¼7.5 Hz), 135.73, 135.02 (d, J¼9.4 Hz), 134.12, 132.37, 132.00 (d,
J¼4.1 Hz), 131.76, 124.60, 124.08, 123.09, 122.40, 122.12, 119.20 (d,
J¼21.5 Hz), 116.99, 112.36, 111.86, 111.77, 107.55, 95.48, 56.43, 56.07,
55.95, 55.43, 37.92, 36.94. HRMS (ESIþ) m/z 596.2057 [(MþNa)þ:
calcd for C33H32FNNaO7, 596.2055].
132.5e133.0 ꢀC; 1H NMR (500 MHz, CDCl3)
d
8.19 (dd, 1H, J¼6.8,
2.2 Hz), 7.77 (ddd, 1H, J¼8.6, 4.0, 2.4 Hz), 7.65e7.53 (m, 5H), 7.31
(dd, 1H, J¼10.1, 9.2 Hz), 5.05 (s, 2H); HRMS (FABþ) m/z 364.0520
[(MþH)þ: calcd for C14H11FN5O4S, 364.0520].
4.1.12. (Z)-2-(4-Fluoro-3-nitrostyryl)-20,4-dimethoxy-40-(3-hydroxy-
4-methoxyphenethyl)biphenyl (4). A solution of 22 (64.9 mg,
0.113 mmol) in 1,4-dioxane (2.0 ml) and 4 M aqueous hydrochloric
acid (2.0 ml) was stirred for 3 h at 70 ꢀC. The reaction mixture was
poured into ethyl acetate and water. The organic layer was washed
4.1.16. (E)-2-(4-Fluoro-3-nitrostyryl)-20,4-dimethoxy-40-[4-methoxy-
3-(methoxymethoxy)phenethyl]biphenyl (28). LiHMDS (1.0
M in
toluene, 0.46 ml, 0.46 mmol) was added to a solution of 27

6080
M. Iwashita et al. / Tetrahedron 67 (2011) 6073e6082
(152 mg, 0.418 mmol) in THF (2 ml) at ꢁ78 ꢀC under argon at-
mosphere, and the mixture was stirred for 30 min at 0 ꢀC.
Thereafter, a solution of 21 (91.3 mg, 0.209 mmol) in THF (1.0 ml)
was added dropwise to the mixture at ꢁ78 ꢀC, and the mixture
was stirred for 3 h at 0 ꢀC. The reaction mixture was poured into
saturated aqueous ammonium chloride, and diluted with ethyl
acetate. The organic layer was washed with saturated aqueous
ammonium chloride and brine, dried with sodium sulfate, and
evaporated. The crude product was purified by silica gel column
chromatography (n-hexane/ethyl acetate 7:3) and following gel
permeation chromatography gave a mixture of 28 and 21 (106 mg,
0.185 mmol, 97%) as yellow oil in a ratio of 16:1. 28: 1H NMR
1H, J¼7.6, 1.3 Hz), 6.24 (d, 1H, J¼2.0 Hz), 6.09 (dd, 1H, J¼8.0, 2.0 Hz),
5.81 (d, 1H, J¼2.0 Hz), 3.88 (s, 3H), 3.84 (s, 3H), 3.61 (s, 3H),
2.84e2.77 (m, 8H); HRMS (ESIþ) m/z 504.2143 [(MþNa)þ: calcd for
C31H31NNaO4, 504.2145].
4.1.20. Riccardin C trimethyl ether (32). Aqueous hydrochloric acid
(4 M, 1.2 ml) was added to a solution of 31 (52.9 mg, 0.110 mmol)
in THF (4.0 ml) at 0 ꢀC, and the mixture was stirred for 15 min at
ambient temperature. A solution of NaNO2 (22.8 mg, 0.330 mmol)
in water (0.5 ml) was added to the mixture at 0 ꢀC, and the
mixture was stirred for 1 h at 0 ꢀC. Then, 30% H3PO2 (242 mg,
1.10 mmol) and Cu2O (15.7 mg, 0.110 mmol) were added to the
mixture, and the mixture was stirred for 10 min at 0 ꢀC, then 4 h at
room temperature. The reaction mixture was diluted with ethyl
acetate, and the organic layer was washed with water and brine,
dried with sodium sulfate, and evaporated. The residue was pu-
rified by silica gel column chromatography (n-hexane/ethyl ace-
tate 6:1) to give 32 (colorless oil, 42.5 mg, 0.091 mmol, 83%). 1H
(500 MHz, CDCl3)
d
7.95 (dd, 1H, J¼7.0, 2.3 Hz), 7.52 (ddd, 1H,
J¼8.6, 4.1, 2.3 Hz), 7.23 (d, 1H, J¼1.6 Hz), 7.22 (d, 1H, J¼8.6 Hz), 7.19
(dd, 1H, J¼10.5, 8.7 Hz), 7.06 (d, 1H, J¼7.5 Hz), 7.02 (d, 1H,
J¼1.7 Hz), 6.94 (s, 2H), 6.92 (dd, 1H, J¼8.5, 2.7 Hz), 6.86 (dd, 1H,
J¼7.6, 1.5 Hz), 6.85 (dd, 1H, J¼8.2, 1.8 Hz), 6.83 (d, 1H, J¼8.2 Hz),
6.78 (d, 1H, J¼1.3 Hz), 5.20 (s, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.69 (s,
3H), 3.50 (s, 3H), 2.99e2.90 (m, 4H); HRMS (FABþ) m/z 574.2249
[(MþH)þ: calcd for C33H32FNO7, 574.2241].
NMR (500 MHz, CDCl3, 353 K)
d
6.94 (d, 1H, J¼8.5 Hz), 6.91 (d, 1H,
J¼2.7 Hz), 6.86 (d, 1H, J¼8.2 Hz), 6.78 (d, 1H, J¼7.6 Hz), 6.76 (d, 2H,
J¼8.8 Hz), 6.73 (dd, 1H, J¼8.5, 2.7 Hz), 6.71 (dd, 1H, J¼8.3, 2.0 Hz),
6.63 (d, 2H, J¼8.6 Hz), 6.45 (d, 1H, J¼1.5 Hz), 6.24 (dd, 1H, J¼7.6,
1.5 Hz), 5.53 (d, 1H, J¼2.1 Hz), 3.83 (s, 3H), 3.81 (s, 3H), 3.58 (s, 3H),
2.91e2.84 (m, 4H), 2.78e2.67 (m, 4H); 13C NMR (125 MHz, CDCl3)
4.1.17. (E)-2-(4-Fluoro-3-nitrostyryl)-20,4-dimethoxy-40-(3-hydroxy-
4-methoxyphenethyl)biphenyl (29). A mixture of 28 and 21 (16:1,
78.3 mg, 0.137 mmol) in THF (3.0 ml) and 4 M aqueous hydrochloric
acid (2.5 ml) was stirred for 3 h at 50 ꢀC. The reaction mixture was
poured into ethyl acetate and brine, and the organic layer was
washed with brine, dried with sodium sulfate, and evaporated.
Purification by silica gel column chromatography (n-hexane/ethyl
acetate 3:1) gave 29 (pale yellow oil, 75.4 mg, 0.142 mmol, quant.)
d
159.11, 155.96, 152.72, 148.64, 146.89, 143.24, 141.20, 139.69,
133.77, 132.42, 132.39, 130.90, 129.54, 127.57, 122.29, 121.68, 121.38,
116.64, 115.36, 111.78, 111.41, 111.14, 56.09, 55.21, 55.19, 38.22,
38.07, 37.23, 35.57; HRMS (ESIþ) m/z 489.2048 [(MþNa)þ: calcd
for C31H30NaO4, 489.2036].
as a mixture of 21 and 4 (16:1). 1H NMR (500 MHz, CDCl3)
d 7.97 (dd,
1H, J¼7.0, 2.2 Hz), 7.55 (ddd, 1H, J¼8.7, 4.1, 2.3 Hz), 7.26e7.23 (m,
3H), 7.19 (dd, 1H, J¼10.5, 8.6 Hz), 7.07 (d, 1H, J¼7.5 Hz), 6.95 (s, 2H),
6.94 (dd, 1H, J¼8.4, 2.6 Hz), 6.87 (dd, 1H, J¼8.1, 1.2 Hz), 6.82e6.77
(m, 2H), 6.71 (dd,1H, J¼8.2, 2.0 Hz), 5.68 (s, 2H), 3.89 (s, 3H), 3.86 (s,
3H), 3.70 (s, 3H), 3.02e2.87 (m, 4H); HRMS (FABþ) m/z 530.1972
[(MþH)þ: calcd for C31H29FNO6, 530.1979].
4.1.21. Riccardin C (1). BBr3 (1.0 M in CH2Cl2, 0.240 ml, 0.240 mmol)
was added to a solution of 32 (18.7 mg, 0.040 mmol) in methylene
chloride (2.0 ml) at ꢁ78 ꢀC and, the mixture was stirred for 2 h at
room temperature. The reaction was poured into methanol at 0 ꢀC,
and diluted with methylene chloride. The organic layer was washed
with water and brine, dried with sodium sulfate, and evaporated.
The residue was purified by silica gel column chromatography (n-
hexane/ethyl acetate 3:2) to give 1 (colorless solids, 13.0 mg,
0.031 mmol, 77%). Mp 192.5e193.0 ꢀC; 1H NMR (500 MHz, CDCl3)
4.1.18. (E)-Macrocyclic ether 30. Potassium carbonate (6.9 mg,
0.050 mmol) and 18-crown-6 (1.1 mg, 0.004 mmol) was added to
a solution of 21 and 2 (16:1, 10.6 mg, 0.020 mmol) in DMF
(2.0 ml), and the mixture was stirred for 2 h at 45 ꢀC. The reaction
mixture was poured into a mixture of ethyl acetate and water. The
organic layer was washed with water and brine, dried with so-
dium sulfate, and evaporated. Purification by silica gel column
chromatography (n-hexane/ethyl acetate 6:1) gave a mixture of
d
7.02 (d, 1H, J¼8.3 Hz), 6.95 (d, 1H, J¼2.6 Hz), 6.90 (d, 1H, J¼8.1 Hz),
6.89e6.73 (m, 2H), 6.79e6.75 (m, 1H), 6.76 (d, 2H, J¼7.7 Hz), 6.72
(dd, 1H, J¼8.1, 1.9 Hz), 6.37 (d, 1H, J¼1.5 Hz), 6.21 (dd, 1H, J¼7.7,
1.6 Hz), 5.62 (br s, 1H), 5.34 (d, 1H, J¼2.1 Hz), 5.14 (br s, 1H), 4.80 (br
s,1H), 3.07e2.99 (m,1H), 2.92e2.82 (m, 2H), 2.80e2.58 (m, 5H); 13C
NMR (125 MHz, CDCl3)
d 155.89, 152.56, 151.81, 146.28, 143.76,
30 and 24 (pale yellow oil, 0.2 mg, 0.40
m
mol, 2%). 1H NMR
143.29, 141.95, 139.80, 133.10, 132.84, 131.37, 129.33, 128.25, 124.38,
122.35, 122.16, 121.68, 117.47, 116.04, 116.03, 114.92, 114.29, 38.08,
37.73, 37.02, 34.95; HRMS (ESIþ) m/z 447.1567 [(MþH)þ: calcd for
C28H24NaO4, 447.1572].
(500 MHz, CDCl3)
d
7.80 (d, 1H (major), J¼2.1 Hz), 7.73 (d, 1H
(minor), J¼2.1 Hz), 7.36 (dd, 1H (minor), J¼8.6, 2.0 Hz), 7.30 (dd,
1H (major), J¼8.6, 2.0 Hz), 7.27e6.77 (m, 8H), 6.66 (d, 1H (major),
J¼7.6 Hz), 6.60 (d, 1H (minor), J¼7.6 Hz), 6.60e6.56 (m, 1H), 6.47
(s, 1H (major)), 6.38 (s, 1H (minor)), 6.16 (d, 1H (major),
J¼16.1 Hz), 6.04 (d, 1H (minor), J¼16.1 Hz), 5.70 (d, 1H (minor),
J¼1.8 Hz), 5.63 (d, 1H (major), J¼1.8 Hz), 3.94 (s, 3H (major)), 3.93
(s, 3H (minor)), 3.87 (s, 3H), 3.69 (s, 3H (major)), 3.64 (s, 3H
(minor)), 3.04e2.65 (m, 4H).
4.1.22. 20,4-Dimethoxy-40-methyl-2-nitrobiphenyl
(34). K3PO4
(5.09 g, 24.0 mmol) and PdCl2(dppf)$CH2Cl2 (327 mg, 0.400 mmol)
was added to a solution of 4-iodo-3-nitroanisole (33, 2.28 g,
8.00 mmol) and 8 (2.18 g, 8.80 mmol) in DMF (30 ml) and water
(0.6 ml) under argon atmosphere, and the mixture was stirred for
3 h at 70 ꢀC. The reaction mixture was filtered through Celite, and
the filtrate was diluted with water, extracted with methylene
chloride. The organic layer was washed with water and brine, dried
with sodium sulfate, and evaporated. The residue was purified by
silica gel column chromatography (n-hexane/ethyl acetate 15:1 to
10:1) to give 34 (orange solid, 1.78 g, 6.52 mmol, 81%). Mp
4.1.19. Macrocyclic amine 31. Palladium on carbon (10%, 5.0 mg)
was added to a solution of 24 (17.9 mg, 0.035 mmol) in THF (0.5 ml)
and MeOH (1.0 ml), and the mixture was stirred for 2 h under hy-
drogen atmosphere. The reaction mixture was filtered through
Celite, and the filtrate was evaporated. The crude was purified by
silica gel column chromatography (n-hexane/ethyl acetate 6:1) to
give 23 (colorless oil,15.5 mg, 0.032 mmol, 92%). 1H NMR (500 MHz,
137.5e138.0 ꢀC; 1H NMR (500 MHz, CDCl3)
d
7.43 (d, 1H, J¼2.6 Hz),
7.28 (d, 1H, J¼8.5 Hz), 7.15 (d, 1H, J¼7.7 Hz), 7.14 (dd, 1H, J¼8.5,
2.7 Hz), 6.87 (d, 1H, J¼7.6 Hz), 6.71 (s, 1H), 3.87 (s, 3H), 3.67 (s, 3H),
453 K, DMSO-d6)
(d, 1H, J¼8.4 Hz), 6.80 (d, 1H, J¼7.5 Hz), 6.80 (m, 1H), 6.77 (dd, 1H,
J¼8.4, 2.7 Hz), 6.57 (d, 1H, J¼1.2 Hz), 6.47 (d, 1H, J¼8.0 Hz), 6.26 (dd,
d
6.95 (d,1H, J¼8.2 Hz), 6.92 (d, 1H, J¼2.7 Hz), 6.92
2.39 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 158.81, 155.73, 150.04,
139.58, 133.23, 129.35, 125.19, 123.94, 121.76, 118.85, 111.55, 108.94,

M. Iwashita et al. / Tetrahedron 67 (2011) 6073e6082
6081
55.78, 55.00, 21.61; HRMS (FABþ) m/z 274.1075 [(MþH)þ: calcd for
methylene chloride (1.0 ml) was added dropwise to a solution of 39
(42.4 mg, 0.100 mmol) in THF (3.0 ml), and the mixture was stirred
at 0 ꢀC. After 1 h, the reaction mixture was poured into methanol at
0 ꢀC, and diluted with ethyl acetate. The organic layer was washed
with water and brine, dried with sodium sulfate, and evaporated.
The residue was purified by silica gel column chromatography (n-
hexane/ethyl acetate 2:1 to 1:1) to give 40 (yellow oil, 56.0 mg,
C15H16NO4, 274.1079].
4.1.23. [(2,40-Dimethoxy-20-nitrobiphenyl-4-yl)methyl]triphenyl-
phosphonium bromide (36). Compound 36 was prepared from 34
(1.36 g, 5.00 mmol) according to the synthetic procedure for 5 from
13. Compound 36: yellow solids,1.75 g, 2.85 mmol, 57% (two steps);
mp 277.5e278.0 ꢀC; 1H NMR (500 MHz, CDCl3)
d
7.78e7.69 (m, 9H),
0.095 mmol, 95%). 1H NMR (500 MHz, CDCl3)
d 8.68 (br s, 1H), 8.24
7.64e7.58 (m, 6H), 7.38 (d, 1H, J¼2.6 Hz), 7.07 (d, 1H, J¼8.5 Hz), 7.01
(dd, 1H, J¼8.5, 2.6 Hz), 6.89 (d, 1H, J¼7.6 Hz), 6.89 (d, 1H, J¼7.6 Hz),
6.85 (t, 1H, J¼1.9 Hz), 6.76 (ddd, 1H, J¼7.5, 2.7, 1.6 Hz), 5.52 (d, 2H,
J¼13.8 Hz), 3.83 (s, 3H), 3.25 (s, 3H); 13C NMR (125 MHz, CDCl3)
(dd, 1H, J¼6.8, 2.2 Hz), 8.12e8.08 (m, 1H), 7.80 (br s, 1H), 7.35 (dd,
1H, J¼10.1, 8.8 Hz), 7.20 (d, 1H, J¼8.5 Hz), 7.14 (d, 1H, J¼8.0 Hz),
6.93e6.91 (m, 3H), 6.83e6.79 (m, 3H), 5.13 (s, 2H), 3.87 (s, 3H), 3.86
(s, 3H), 3.83 (s, 3H), 3.45 (s, 3H), 2.99e2.85 (m, 4H); 13C NMR
d
159.14, 155.92, 149.93, 134.75 (d, 6C, J¼2.9 Hz), 134.66, 133.11,
(125 MHz, CDCl3)
d
161.44, 159.54, 157.26 (d, J¼270.9 Hz), 155.29,
130.06 (d, 6C, J¼11.6 Hz), 129.52 (d, J¼3.8 Hz), 128.76 (d, J¼8.6 Hz),
126.98 (d, J¼4.6 Hz), 124.62, 123.69 (d, J¼5.6 Hz), 118.71, 117.94 (d,
J¼85.7 Hz), 114.90 (d, J¼5.2 Hz), 109.29, 55.83, 55.49, 30.72 (d,
J¼46.3 Hz); HRMS (FABþ) m/z 534.1848 [(MꢁBrꢁ)þ: calcd for
C33H29NO4P, 534.1834].
148.05, 146.25, 143.91, 136.77 (d, J¼7.6 Hz), 135.70, 135.02 (d,
J¼9.6 Hz),134.09,132.36,131.97 (d, J¼3.8 Hz),131.76,124.56,124.06,
123.08, 122.37, 122.09, 119.19 (d, J¼21.4 Hz), 116.91, 112.31, 111.77 (d,
J¼7.4 Hz), 107.53, 95.44, 56.40, 56.06, 55.92, 55.41, 37.92, 36.93;
HRMS (FABþ) m/z 591.2156 [(MþH)þ: calcd for C32H32FN2O8,
591.2143].
4.1.24. 20,4-Dimethoxy-40-[4-methoxy-3-(methoxymethoxy)styryl]-
2-nitrobiphenyl [37 (E isomer) and 38 (Z isomer)]. Compounds 37
and 38 were prepared from 36 (1.61 g, 2.63 mmol) and 6 (491 mg,
2.50 mmol) according to the synthetic procedure for 17 and 18 from
5. Compound 37: yellow oil, 499 mg, 1.11 mmol, 44%; 1H NMR
4.1.27. 2-(4-Fluoro-3-nitrobenzamido)-20,4-dimethoxy-40-[3-
hydroxy-4-methoxyphenethyl]biphenyl (41). A solution of com-
pound 40 (51.2 mg, 0.087 mmol) in THF (3.0 ml) and 4 M aqueous
hydrochloric acid (1.0 ml) was stirred for 2 h at 50 ꢀC. The reaction
mixture was poured into ethyl acetate and water. The organic
layer was washed with water and brine, dried with sodium sul-
fate, and evaporated. The residue was purified by silica gel column
chromatography (n-hexane/ethyl acetate 1:1) to give 41 (yellow
solids, 41.3 mg, 0.076 mmol, 87%). Mp 191.0e191.5 ꢀC; 1H NMR
(500 MHz, CDCl3)
d
7.44 (d,1H, J¼2.7 Hz), 7.35 (d,1H, J¼2.0 Hz), 7.29
(d, 1H, J¼8.5 Hz), 7.23 (d, 1H, J¼7.8 Hz), 7.16 (dd, 1H, J¼7.8, 1.1 Hz),
7.13 (m, 2H), 7.05 (d, 1H, J¼16.3 Hz), 6.99 (d, 1H, J¼1.0 Hz), 6.96 (d,
1H, J¼16.3 Hz), 6.87 (d, 1H, J¼8.4 Hz), 5.28 (s, 2H), 3.88 (s, 3H), 3.86
(s, 3H), 3.73 (s, 3H), 3.55 (s, 3H); 13C NMR (125 MHz, CDCl3)
d
158.89, 156.05, 149.94, 149.62, 146.65, 138.88, 133.09, 130.34,
(500 MHz, CDCl3)
d
8.78 (br s, 1H), 8.35 (dd, 1H, J¼7.0, 2.2 Hz),
129.70, 128.71, 126.53, 125.88, 124.88, 121.24, 119.41, 118.82, 114.05,
111.75, 108.98, 108.12, 95.47, 56.17, 55.88, 55.74, 55.04; HRMS
(FABþ) m/z 451.1622 [Mþ: calcd for C25H25NO7, 451.1631]. Com-
pound 38: yellow oil, 439 mg, 0.972 mmol, 39%; 1H NMR (500 MHz,
8.06 (ddd, 1H, J¼8.5, 4.0, 2.2 Hz), 7.79 (d, 1H, J¼1.5 Hz), 7.57 (s,
1H), 7.50 (dd, 1H, J¼10.7, 8.7 Hz), 7.17 (d, 1H, J¼8.6 Hz), 7.15 (d, 1H,
J¼8.1 Hz), 7.00 (br s, 1H), 6.93 (dd, 1H, J¼7.7, 1.2 Hz), 6.78 (dd, 1H,
J¼8.5, 2.6 Hz), 6.69 (d, 1H, J¼2.0 Hz), 6.60 (dd, 1H, J¼8.1, 2.1 Hz),
3.82 (s, 3H), 3.79 (s, 6H), 2.95e2.90 (m, 2H), 2.87e2.82 (m, 2H);
CDCl3)
d
7.42 (d, 1H, J¼2.7 Hz), 7.27 (d, 1H, J¼8.5 Hz), 7.14 (d, 1H,
J¼7.8 Hz), 7.13 (dd, 1H, J¼8.5, 2.7 Hz), 7.09 (d, 1H, J¼2.0 Hz), 6.96
(dd, 1H, J¼7.7, 1.3 Hz), 6.94 (dd, 1H, J¼8.5, 2.1 Hz), 6.80 (d, 1H,
J¼1.3 Hz), 6.78 (d, 1H, J¼8.4 Hz), 6.54 (d, 1H, J¼12.2 Hz), 6.50 (d, 1H,
J¼12.2 Hz), 5.07 (s, 2H), 3.87 (s, 3H), 3.84 (s, 3H), 3.49 (s, 3H), 3.41 (s,
13C NMR (125 MHz, CDCl3)
d
162.29, 160.41, 157.90 (d, J¼277.5 Hz),
157.05, 147.79, 146.80, 144.88, 138.02 (d, J¼7.7 Hz), 137.51, 135.58,
135.48 (d, J¼10.4 Hz), 133.44 (d, J¼3.8 Hz), 132.84, 132.45, 125.66
(d, J¼20.8 Hz), 124.64, 122.39, 119.62 (d, J¼21.7 Hz), 119.57, 116.36,
112.82, 112.05, 111.47, 109.34, 56.21 (2C), 55.56, 38.94, 37.99;
HRMS (FABþ) m/z 547.1867 [(MþH)þ: calcd for C30H28FN2O7,
547.1881].
3H); 13C NMR (125 MHz, CDCl3)
d 158.93, 155.59, 150.12, 149.12,
145.98, 138.73, 133.11, 130.25, 129.90, 129.40, 128.71, 125.58, 124.99,
123.36, 121.88, 118.88, 117.22, 111.43, 110.94, 108.93, 95.47, 56.06,
55.84, 55.80, 54.89; HRMS (FABþ) m/z 451.1643 [Mþ: calcd for
C25H25NO7, 451.1631].
4.1.28. Macrolactam
42. Potassium
carbonate
(106
mg,
0.768 mmol) and 18-crown-6 (12.1 mg, 0.051 mmol) was added to
a solution of 41 (140 mg, 0.256 mmol) in DMF (25 ml), and the
mixture was stirred for 2 h at 45 ꢀC. The reaction mixture was
poured into ethyl acetate and water. The organic layer was washed
with water and brine, dried with sodium sulfate, and evaporated.
The residue was purified by silica gel column chromatography (n-
hexane/ethyl acetate 3:1 to 1:1) gave 42 (pale yellow solids,
99.8 mg, 0.190 mmol, 74%). Mp 176.5e177.0 ꢀC; 1H NMR (500 MHz,
4.1.25. 2-Amino-20,4-dimethoxy-40-[4-methoxy-3-(methoxymethoxy)
phenethyl]biphenyl (39). Pd(OH)2 on carbon (10%, 50.0 mg) was
added to a solution of 38 (459 mg, 1.02 mmol) in THF (10 ml) and
methanol (20 ml), and the mixture was stirred for 1 day under
hydrogen atmosphere. The reaction mixture was filtered through
Celite and the filtrate was evaporated. The residue was purified by
silica gel column chromatography (n-hexane/ethyl acetate 7:3) to
give 39 (colorless oil, 364 mg, 0.860 mmol, 85%). 1H NMR (500 MHz,
CDCl3)
d 8.20e8.17 (m, 1H), 7.88e7.58 (m, 2H), 7.46e7.35 (m, 1H),
CDCl3)
d
7.13 (d, 1H, J¼7.6 Hz), 6.99 (d, 1H, J¼8.4 Hz), 6.98 (s, 1H),
7.21e6.74 (m, 7H), 6.62e6.46 (m, 1H), 5.61e5.45 (m, 1H), 3.96e3.94
(m, 3H), 3.88 (s, 3H), 3.85e3.70 (m, 3H), 3.12e2.91 (m, 2H),
2.82e2.61 (m, 2H); HRMS (FABþ) m/z 527.1832 [(MþH)þ: calcd for
C30H27N2O7, 591.2143].
6.85 (dd, 1H, J¼7.6, 1.4 Hz), 6.83 (d, 1H, J¼1.0 Hz), 6.75 (d, 1H,
J¼1.1 Hz), 6.39 (dd, 1H, J¼8.4, 2.5 Hz), 6.31 (d, 1H, J¼2.4 Hz), 5.19 (s,
2H), 3.85 (s, 3H), 3.78 (s, 3H), 3.75 (s, 3H), 3.73e3.65 (br s, 2H), 3.51
(s, 3H), 2.95e2.86 (m, 4H); 13C NMR (125 MHz, CDCl3)
d 159.94,
156.66, 148.06, 146.32, 145.53, 142.58, 134.47, 131.92, 131.79, 125.54,
122.12, 121.10, 117.84, 116.95, 111.82, 111.62, 103.99, 101.14, 95.57,
56.12, 55.96, 55.65, 55.05, 38.08, 37.14.
4.1.29. Macrolactam 43. Palladium on carbon (10%, 20.0 mg) was
added to a solution of 42 (62.5 mg, 0.012 mmol) in DMF (5.0 ml),
and the mixture was stirred for 2 h under hydrogen atmosphere.
The reaction mixture was filtered through Celite, and the filtrate
was diluted with ethyl acetate. The organic layer was washed with
water and brine, dried with sodium sulfate, and evaporated. The
residue was purified by silica gel column chromatography (n-
hexane/ethyl acetate 3:2 to 2:3) to give 43 (colorless oil, 52.1 mg,
4.1.26. 2-(4-Fluoro-3-nitrobenzamido)-20,4-dimethoxy-40-[4-
methoxy-3-(methoxymethoxy)phenethyl]biphenyl (40). A solution of
4-fluoro-3-nitrobenzoyl chloride (30.5 mg, 0.150 mmol, prepared
from 4-fluoro-3-nitrobenzoic acid and oxalyl chloride) in

6082
M. Iwashita et al. / Tetrahedron 67 (2011) 6073e6082
0.105 mmol, 88%). 1H NMR (500 MHz, CDCl3)
d
7.70e7.40 (m, 1H),
(s, 3H), 3.50 (s, 3H), 2.89e2.75 (m, 2H), 2.74 (m, 2H); HRMS
7.40e7.37 (m, 1H), 7.16e7.12 (m, 1H), 6.98e6.88 (m, 3H),
6.86e6.73 (m, 4H), 6.48e6.40 (m, 1H), 5.88e5.70 (m, 1H), 3.94 (s,
3H), 3.88 (s, 3H), 3.90e3.85 (m, 1H), 3.10e2.85 (m, 2H), 2.78e2.54
(m, 2H).
(FABþ) m/z 496.2130 [(MþH)þ: calcd for C31H30NO5, 496.2124].
4.1.33. N-Methylmacrolactam 3. Compound 3 was prepared from
45 (9.8 mg, 0.020 mmol) according to the synthetic procedure for 1
from 32. Compound3: colorless solids, 6.5 mg, 0.014 mmol, 72%; mp
4.1.30. Trimethoxymacrolactam 44. Aqueous hydrochloric acid
(4 M, 1.0 ml) was added to a solution of 43 (46.7 mg, 0.094 mmol) in
THF (4.0 ml) at 0 ꢀC, and the mixture was stirred for 15 min at
ambient temperature. A solution of NaNO2 (19.5 mg, 0.283 mmol)
in water (0.5 ml) was added to the mixture at 0 ꢀC, and the mixture
was stirred for 1 h at 0 ꢀC. 50% H3PO2 (124 mg, 0.941 mmol) and
Cu2O (13.5 mg, 0.094 mmol) were added, and the mixture was
stirred for 10 min at 0 ꢀC, then 3 h at room temperature. The re-
action mixture was diluted with ethyl acetate, and the organic layer
was washed with water and brine, dried with sodium sulfate, and
evaporated. The residue was purified by silica gel column chro-
matography (n-hexane/ethyl acetate 3:1) gave 44 (colorless oil,
228.5e229.0 ꢀC; 1H NMR (500 MHz, acetone-d6)
d 8.62 (br s, 1H),
7.87e7.75 (br m, 3H), 7.09 (br s, 1H), 7.01 (d, 1H, J¼2.5 Hz),
6.87e6.78 (m, 2H), 6.84 (dd,1H, J¼8.9, 2.5 Hz) 6.81 (d,1H, J¼8.1 Hz),
6.70 (dd, 1H, J¼8.1, 2.0 Hz), 6.38e6.33 (br m, 2H), 5.25 (br s, 1H),
3.56 (s, 3H), 2.76e2.50 (m, 4H); HRMS (FABþ) m/z 454.1664
[(MþH)þ: calcd for C8H24NO5, 454.1654].
Acknowledgements
The work described in this paper was partially supported by
Grants-in-Aid for Scientific Research from The Ministry of Educa-
tion, Science, Sports and Culture, Japan (Grant Nos 22790106 to T.H.,
19201044 to H.K.). Authors are grateful to Prof. Yoshinori Asakawa
and Prof. Toshihiro Hashimoto, Tokushima Bunri University, for
a generous gift of the authentic sample of Riccardin C.
30.6 mg, 0.064 mmol, 68%). 1H NMR (500 MHz, CDCl3)
d 7.54 (dd,
1H, J¼8.2, 2.2 Hz), 7.53 (m, 1H), 7.48 (dd, 1H, J¼8.4, 2.2 Hz), 7.45 (d,
1H, J¼2.7 Hz), 7.14 (d,1H, J¼8.4 Hz), 7.02 (dd,1H, J¼8.4, 2.3 Hz), 6.98
(dd, 1H, J¼8.4, 2.3 Hz), 6.94 (d, 1H, J¼7.7 Hz), 6.90 (d, 1H, J¼8.3 Hz),
6.84 (dd, 1H, J¼8.3, 2.0 Hz), 6.78 (dd, 1H, J¼8.4, 2.7 Hz), 6.76 (dd, 1H,
J¼7.7, 1.1 Hz), 6.50 (d, 1H, J¼0.8 Hz), 5.63 (d, 1H, J¼2.0 Hz), 3.94 (s,
3H), 3.87 (s, 3H), 3.71 (s, 3H), 3.03 (dd, 1H, J¼14.3, 9.3 Hz), 2.97 (dd,
1H, J¼14.0, 9.3 Hz), 2.77 (dd, 1H, J¼14.0, 10.4 Hz), 2.66 (dd, 1H,
References and notes
1. (a) Zinsmeister, H. D.; Becker, H.; Eicher, T. Angew. Chem., Int. Ed. Engl. 1991, 30,
130e147; (b) Asakawa, Y. Phytochemistry 2001, 56, 297e312; (c) Asakawa, Y.;
Toyota, M.; Hashimoto, T.; Tori, M.; Nagashima, F.; Harinantenaina, L. Hetero-
cycles 2008, 76, 99e127.
2. Asakawa, Y.; Matsuda, R. Phytochemistry 1982, 21, 2143e2144.
3. Tamehiro, N.; Sato, Y.; Suzuki, T.; Hashimoto, T.; Asakawa, Y.; Yokoyama, S.;
Kawanishi, T.; Ohno, Y.; Inoue, K.; Nagao, T.; Nishimaki-Mogami, T. FEBS Lett.
2005, 579, 5299e5304.
4. (a) Collins, J. L. Curr. Opin. Drug Discovery Dev. 2004, 7, 692e702; (b) Bennett, D.
J.; Carswell, E. L.; Cooke, A. J.; Edwards, A. S.; Nimz, O. Curr. Med. Chem. 2008, 15,
195e209; (c) Goodwin, B. J.; Zuercher, W. J.; Collins, J. L. Curr. Top. Med. Chem.
2008, 8, 781e791.
J¼14.3, 10.4 Hz); 13C NMR (125 MHz, CDCl3)
d 166.99, 159.75,
158.93, 155.50, 149.36, 147.90, 143.52, 137.00, 135.26, 133.62, 132.09,
130.41, 128.65, 126.82, 124.27, 123.97, 123.36, 122.63, 122.18, 121.45,
117.17, 112.46, 111.73, 111.45, 108.13, 56.21, 55.92, 55.48, 36.83,
34.69; HRMS (FABþ) m/z 482.1958 [(MþH)þ: calcd for C30H28NO5,
591.2143].
4.1.31. Macrolactam 2. Compound 2 was prepared from 44 (9.6 mg,
0.020 mmol) according to the synthetic procedure for 1 from 32.
Compound2: colorless oil, 7.8 mg, 0.018 mmol, 89%; 1H NMR
5. (a) Kodama, M.; Shiobara, Y.; Matsumura, K.; Sumitomo, H. Tetrahedron Lett.
1985, 26, 877e880; (b) Iyoda, M.; Sakaitani, M.; Otsuka, H.; Oda, M. Tetrahedron
Lett. 1985, 26, 4777e4780; (c) Kodama, M.; Shiobara, Y.; Sumitomo, H.;
Matsumura, K.; Tsukamoto, M.; Harada, C. J. Org. Chem. 1988, 53, 72e77; (d)
Fukuyama, Y.; Yaso, H.; Nakamura, K.; Kodama, M. Tetrahedron Lett. 1999, 40,
105e108; (e) Fukuyama, Y.; Kodama, M.; Asakawa, Y. J. Synth. Org. Chem. 2000,
58, 654e665; (f) Esumi, T.; Wada, M.; Mizushima, E.; Sato, N.; Kodama, M.;
Asakawa, Y.; Fukuyama, Y. Tetrahedron Lett. 2004, 45, 6941e6945; (g) Speicher,
A.; Groh, M.; Hennrich, M.; Huynh, A.-M. Eur. J. Org. Chem. 2010, 6760e6778.
(500 MHz, THF-d8)
d
8.40 (d, 1H, J¼2.0 Hz), 8.26 (s, 2H), 7.69 (s, 1H),
7.61 (d, 1H, J¼8.4 Hz), 7.49 (d, 1H, J¼8.3 Hz), 7.37 (d, 1H, J¼2.5 Hz),
7.02 (d, 2H, J¼8.3 Hz), 6.91 (dd, 1H, J¼8.4, 1.9 Hz), 6.82 (d, 1H,
J¼7.8 Hz), 6.80 (d, 1H, J¼8.2 Hz), 6.76 (dd, 1H, J¼8.2, 2.0 Hz), 6.62
(dd, 1H, J¼7.7, 1.5 Hz), 6.57 (dd, 1H, J¼8.2, 2.5 Hz), 6.38 (d, 1H,
J¼1.3 Hz), 5.68 (d, 1H, J¼2.0 Hz), 2.95e2.87 (m, 2H), 2.68e2.58 (m,
ꢀ
ꢀ
ꢀ
6. (a) Gottsegen, A; Nogradi, M.; Vermes, B. Tetrahedron Lett. 1988, 29,
ꢀ
ꢀ
ꢀ
5039e5040; (b) Gottsegen, A; Nogradi, M.; Vermes, B. J. Chem. Soc., Perkin Trans.
1 1990, 315e320.
2H); 13C NMR (125 MHz, THF-d8)
d 166.62, 160.74, 158.69, 154.30,
€
7. Eicher, T.; Fey, S.; Puhl, W.; Buchel, E.; Speicher, A. Eur. J. Org. Chem.1998, 877e888.
8. Dodo, K.; Aoyama, A.; Noguchi-Yachide, T.; Makishima, M.; Miyachi, M.;
Hashimoto, Y. Bioorg. Med. Chem. 2008, 16, 4272e7285.
148.57, 147.17, 143.90, 138.52, 135.34, 134.60, 132.80, 131.21, 129.24,
128.12, 124.79, 123.73, 122.92, 122.74, 122.33, 121.28, 119.15, 117.52,
117.19, 112.16, 109.82, 37.80, 35.81; HRMS (FABþ) m/z 440.1494
[(MþH)þ: calcd for C27H22NO5, 440.1498].
9. Harrowven, D. C.; Woodcock, T.; Howes, P. D. Angew. Chem., Int. Ed. 2005, 44,
3899e3901.
10. Hioki, H.; Shima, N.; Kawaguchi, K.; Harada, K.; Kubo, M.; Esumi, T.; Nishimaki-
Mogami, T.; Sawada, J.; Hashimoto, T.; Asakawa, Y.; Fukuyama, Y. Bioorg. Med.
Chem. Lett. 2009, 19, 738e741.
4.1.32. N-Methylmacrolactam 45. Sodium hydride (60% in mineral
oil, 2.0 mg, 0.050 mmol) was added to a solution of 44 (13.4 mg,
0.028 mmol) in DMF (2.0 ml), and the mixture was stirred for
10 min at 0 ꢀC. Iodomethane (28.4 mg, 0.20 mmol) was added to
the reaction vessel, and the mixture was stirred for 1 h at 0 ꢀC.
The reaction mixture was poured into water at 0 ꢀC, and diluted
with ethyl acetate and water. The organic layer was washed with
brine, dried with sodium sulfate, and evaporated. The residue was
purified by silica gel column chromatography (n-hexane/ethyl
acetate 2:1) to give 45 (colorless wax, 14.2 mg, 0.029 mmol,
11. (a) Zhu, J. Synlett 1997, 133e144; (b) Sawyer, J. S. Tetrahedron 2000, 56,
5045e5065; (c) Frlan, R.; Kikelj, D. Synthesis 2006, 14, 2271e2285.
12. Selected examples: (a) Beugelmans, R.; Bigot, A.; Zhu, J. Tetrahedron Lett. 1994,
35, 5649e5652; (b) Gonzalez, G.-I.; Zhu, J. J. Org. Chem. 1999, 64, 914e924; (c)
Masuno, M.-N.; Pessah, I. N.; Olmstead, M. M.; Molinski, T. F. J. Med. Chem. 2006,
49, 4497e4511.
13. Boration: Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem.1995, 60, 7508e7510.
14. Ozaki, S.; Adachi, M.; Sekiya, S.; Kamikawa, R. J. Org. Chem. 2003, 68, 4586e4589.
15. Arnusch, C. J.; Pieters, R. J. Eur. J. Org. Chem. 2003, 3131e3138.
16. Boden, R. M. Synthesis 1975, 784.
17. Heynekamp, J. J.; Weber, W. M.; Hunsaker, L. A.; Gonzales, A. M.; Orlando, R. A.;
Deck, L. M.; Jagt, D. L. V. J. Med. Chem. 2006, 49, 7182e7189.
18. Xie, Z.; Yang, B.; Li, F.; Cheng, G.; Liu, L.; Yang, G.; Xu, H.; Ye, L.; Hanif, M.; Liu, S.; Ma,
D.; Ma, Y. J. Am. Chem. Soc. 2005,127,14152e14153; (b) Hwang, J.-J.; Lin, R.-L.; Shieh,
R.-L.; Jwo, J.-J. J. Mol. Catal. A: Chem.1999, 142, 125e139; (c) Xie, Z.; Yang, B.; Liu, L.;
Li, M.; Lin, D.; Ma, Y.; Cheng, G.; Liu, S. J. Phys. Org. Chem. 2005, 18, 962e973.
19. Jourdant, A.; Gonzalez-Zamora, E.; Zhu, J. J. Org. Chem. 2002, 67, 3163e3164.
20. Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998, 26e28.
21. Gallou-Dagommer, I.; Gastaud, P.; RajanBabu, T. V. Org. Lett. 2001, 3, 2053e2056.
quant.); 1H NMR (500 MHz, THF-d8, 353 K)
d 7.48 (br s), 7.15 (d,
1H, J¼8.6 Hz), 7.02 (d, 1H, J¼2.7 Hz), 6.87 (dd, 1H, J¼8.6, 2.7 Hz),
6.85 (d, 1H, J¼8.0 Hz), 6.76 (d, 1H, J¼8.2 Hz), 6.73e6.69 (d, 2H,
J¼8.9 Hz), 6.72 (dd, 1H, J¼8.2, 2.0 Hz), 6.40 (s, 1H), 6.32 (dd, 1H,
J¼7.8, 1.4 Hz), 5.39 (d, 1H, J¼2.1 Hz), 3.85 (s, 3H), 3.84 (s, 3H), 3.64