Concise synthesis of arylnaphthalene lignans by regioselective intramolecular anionic diels-alder reactions of 1,7-diaryl-1,6-diynes

Article abstract of DOI:10.1055/s-0033-1339184

Total synthesis of phyllamycin A and C, justicidin B, and retrojusticidin B from simple arylalkynyl alcohols and (3,4-methylenedioxyphenyl)propynal was accomplished in 4-5 steps by employing an intramolecular anionic Diels-Alder reaction as the key step.

Full text of DOI:10.1055/s-0033-1339184

LETTER
▌1509
lCettoerncise Synthesis of Arylnaphthalene Lignans by Regioselective Intra-
molecular Anionic Diels–Alder Reactions of 1,7-Diaryl-1,6-diynes
Concise Synthesis of Arylnaphthalene Lignans
Takayuki Kudoh,*a Ai Shishido,a Kyohei Ikeda,a Seiki Saito,*a Teruhiko Ishikawab
a
Graduate School of Natural Science and Technology Tsushima, Okayama, 700-8530, Japan
E-mail: kudoh@cc.okayama-u.ac.jp
b
Graduate School of Education, Okayama University Tsushima, Okayama, 700-8530, Japan
Received: 10.04.2013; Accepted after revision: 14.05.2013
hibitory activity against HIV-1 reverse transcriptase.4
Therefore, it is important to develop a highly regioselec-
tive method for the construction of the arylnaphthalene
and fused lactone moieties in arylnaphthalene lignans.
Abstract: Total synthesis of phyllamycin A and C, justicidin B, and
retrojusticidin B from simple arylalkynyl alcohols and (3,4-methy-
lenedioxyphenyl)propynal was accomplished in 4–5 steps by em-
ploying an intramolecular anionic Diels–Alder reaction as the key
step.
Many synthetic routes to arylnaphthalene lignans have
been developed, such as Stobbe/Claisen condensations,5
rearrangement of aryl(gem-dihalocyclopropyl)metha-
nols,6 nucleophilic addition of aryl lithiums to naphthy-
loxazolines,7 conjugate addition–aldol reactions,8 Pd-
catalyzed [2+2+2] cocyclization of arynes and diynes,9
gold-catalyzed intramolecular sequential electrophilic ad-
dition and benzannulation,10 and Diels–Alder reac-
tions.11,12 Among them, the intramolecular Diels–Alder
reaction of the 1,7-diaryl-1,6-diyne system by Klemm’s
group11a and Stevenson’s group11b–d is one of the most
straightforward and efficient approaches to arylnaphtha-
lene lignans (Scheme 1). However, in this system, the sub-
stituted phenylethynyl units can serve as both the diene
and dienophile in the Diels–Alder reaction; thus two
regioisomers may arise through transition state A and B
Key words: lignan, natural products, total synthesis, Diels–Alder
reaction, carbanions
Arylnaphthalene lignans are widely occurring natural
products isolated from plant species. They consist of var-
ious alkoxy-substituted arylnaphthalenes with regioiso-
merically fused lactones (A and B in Figure 1) and exhibit
a broad range of biological activities (Figure 1).1 As a re-
sult, they have attracted attention as lead compounds for
novel drugs. Interestingly, arylnaphthalene lignans with
regioisomerically fused lactones exhibit completely dif-
ferent biological activity. For example, justicidin B (3) in-
hibit calcium release from fetal long-bone cultures2 and
exhibits antiviral activity.3 Meanwhile, the corresponding
retrofused lactone isomer, retrojusticidin B (4) exhibits in-
R1
O
O
O
OR1
OR1
O
O
R2
O
‡
‡
R1
R1
OR2
OR2
A
B
O
O
Z
Z
O
O
O
OMe
OMe
OMe
OMe
R2
R2
O
O
A
B
O
Diels–Alder reaction
O
O
O
O
O
R1
R2
O
O
phyllamycin C (1); Z = OMe
justicidin B (3); Z = H
phyllamycin A (2); Z = OMe
retrojusticidin B (4); Z = H
O
Figure 1 Representative examples of arylnaphthalene lignan natural
products
R2
R1
regioisomers
SYNLETT 2013, 24, 1509–1512
Advanced online publication: 21.06.2013
DOI: 10.1055/s-0033-1339184; Art ID: ST-2013-U0319-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
Scheme 1 Diels–Alder approach for the synthesis of arylnaphtha-
lene lignans using 1,7-diaryl-1,6-diyne

1510
T. Kudoh et al.
LETTER
in Scheme 1. Moreover, if a diyne with an unsymmetric propargylic position in III. The cycloaddition precursor
phenyl substituent is used, two additional regioisomers III would be obtained from the mixed acetal condensation
may form. This lack of selectivity makes the intramolecu- of aldehyde 6 with alcohol 5. This acetal moiety would be
lar Diels–Alder approach difficult to apply to the synthe- expected to work as the key for controlling the regioselec-
sis of differentially substituted arylnaphthalene lignans. In tivity of the IMADA and the regioselective construction
this study, we present a novel process for the selective of the lactone. The requisite alcohols 5 are easily synthe-
synthesis of differentially substituted arylnaphthalene lig- sized by the Sonogashira coupling of the corresponding
nans by the intramolecular anionic Diels–Alder reaction aryl halides with 2-propyn-1-ol, and aldehyde 6 is avail-
(IMADA)13 of 1,7-diaryl-1,6-diynes containing an acetal able by the oxidation of arylalkynyl alcohols prepared by
linker.
Sonogashira coupling reactions.14
The synthesis of the IMADA precursors is depicted in
Scheme 3. In preliminary experiments, the acid-catalyzed
acetalization of (3,4-methylenedioxyphenyl)propynal (6)
with an excess of the corresponding alcohols 5a and 5b in
the presence of trimethyl orthoformate gave 7a and 7b, re-
spectively, in good yields (7a: 79%, 7b: 63%) based on
the recovered dimethyl acetal of 6 (72% for 7a, 37% for
7b). The recovered alcohols 5a and 5b and the dimethyl
acetal of 6 can be reused for the synthesis of 7a and 7b.
O
R1
R1
O
O
O
R2
R2
R1
R2
O
R1
O
O
R3
+
MeO
O
HO
5a, 5b
6
CSA, HC(OMe)3
THF 50 °C 1 d
R2
I
anionic
Diels–Alder
R1
R2
–
R1
R3
–
••
C
O
R1
O
O
O
MeO
7a R1 = R2 = R3 = OMe
79% based on the recovered dimethyl acetal of 6
7b R1 = H, R2 = R3 = OMe
MeO
O
MeO
R2
R2
II
base
63% based on the recovered dimethyl acetal of 6
R1
Scheme 3 Synthesis of cycloaddition precursors 7a and 7b
O
regiocontrol for
cycloaddition and
lactone formation
With the cycloaddition precursors in hand, we attempted
the synthesis of phyllamycin C (1) and phyllamycin A (2,
Scheme 4). These compounds were isolated from Phyl-
lanthus myrtifolius in 1995 and are relatively new aryl-
naphthalene lignans.15 The IMADA of 7a smoothly
proceeded following treatment with 120 mol%
(C6H5CH2)(CH3)3N+OH– (Triton B) in DMSO at room
temperature and gave the desired product 8a in excellent
yield.16 To synthesize 1 from 8a, we examined the trans-
formation of the acetal moiety of 8a to the lactone. The
acidic hydrolysis of 8a to the hemiacetal followed by ox-
idation using iodine under basic conditions gave 1 in 73%
yield. Next, we attempted to synthesize 2, which is the
lactone regioisomer of 1. After the acidic hydrolysis of 8a,
the resultant hemiacetal was immediately reduced to the
corresponding diol with NaBH4. The obtained crude diol
was then oxidized to the lactone with manganese dioxide
(MnO2). Oxidation preferentially occurred at the less ste-
rically hindered alcohol to provide a 5:1 mixture of 2 and
MeO
R2
III
Sonogashira
coupling
acetalization
Sonogashira
coupling
R1
+
O
R2
HO
5
6
oxidation
Scheme 2 Synthetic plan for the preparation of arylnaphthalene lig-
nans by the anionic Diels–Alder reaction of 1,6-diaryldiynes
Our synthetic plan is illustrated in Scheme 2. Both isomer-
ic arylnaphthalene lignans with regioisomeric fused lac-
tones would be synthesized by the oxidation of I. The
substituted arylnaphthalene ring of I would be constructed
via the IMADA of an anion containing the activated diene
II, which would be formed by the deprotonation of the
Synlett 2013, 24, 1509–1512
© Georg Thieme Verlag Stuttgart · New York

LETTER
Concise Synthesis of Arylnaphthalene Lignans
1511
1 in 71% combined yield. The mixture was carefully pu-
7b
1
rified by column chromatography to give pure 2. All H
Triton B
DMSO, r.t., 23 h
NMR and 13C NMR data for synthesized 1 and 2 were
identical to the data reported in the literature for the natu-
ral compounds.15a,17,18 Thus, we achieved the first total
synthesis of 1 and 2.
OMe
O
O
MeO
OMe
OMe
OMe
OMe
MeO
OMe
O
Triton B
DMSO, r.t., 24 h
OMe
O
O
7a
MeO
O
O
8b 65%
8b' 22%
PTSA
THF–H2O
r.t., 2 h
O
a) i) PTSA, THF–H2O
r.t., 2 h
ii) NaBH4, 0 °C, 1 h
b) MnO2, CH2Cl2
r.t., 3 d
O
i) PTSA, THF–H2O
r.t., 0.5 h
ii) I2, K2CO3
r.t., 16 h
8a 92%
OMe
OMe
OMe
OMe
OMe
NaBH4
0 °C
25 min
HO
HO
justicidin B (3)
85% from 8b
retrojusticidin B (4)
50% from 8b
O
OMe
+
HO
3 9% from 8b
Scheme 5 Synthesis of justicidin B (3) and retrojusticidin B (4)
O
O
O
O
Acknowledgment
9 79% from 8a
This research was financially supported by JSPS KAKENHI Grant
Number 18750089 and the Okayama Foundation for Science and
Technology.
MnO2
CH2Cl2, r.t.
36 h
I2, K2CO3
r.t., 24 h
phyllamycin C (1)
73% from 8a
phyllamycin A (2)
71% (2/1 = 5:1) from 8a
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
Scheme 4 Synthesis of phyllamycin C (1) and phyllamycin A (2)
Encouraged by these results, we next attempted to synthe-
size 3 and 4 (Scheme 5). The IMADA of 7b provided a
mixture of the two differently substituted arylnaphtha-
lenes 8b and 8b′ in high yield (8b: 65% yield, 8b′: 22%
yield). These two products must have arisen from the re-
action of two different dienes containing an allene moiety
generated as the result of the isomerization of the alkyne
and the contiguous π bond of the 3,4-dimethoxyphenyl
substituent in 7b. After the chromatographic separation of
these two products, the transformation of 8b into 3 and 4
was examined. Following the same transformation proce-
dure as used for the synthesis of 1 and 2, we succeeded in
synthesizing 3 in 85% from 8b in one step and 4 in 50%
References and Notes
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isolated yield from 8b in two steps. All 1H NMR and 13
C
NMR data for synthesized 3 and 4 were identical to the
data reported in the literature.5c,19,20
Motoyoshiya, J.; Aoyama, H.; Tanabe, Y. J. Org. Chem.
2005, 70, 2667.
In conclusion, we demonstrated the concise total synthesis
of 4-arylnaphthalene lignans using IMADA as the key
transformation. Our synthetic process requires only 4–5
steps from easily synthesizable arylalkynyl alcohols and
arylalkynyl aldehydes. It is applicable to the synthesis of
a wide variety of arylnaphthalene lignan natural products
simply by changing the combination of starting alcohols
and aldehydes.
(7) (a) Meyers, A. I.; Fiisak, J. R.; Aitken, R. A. J. Am. Chem.
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Ohmizu, H.; Iwasaki, T. Tetrahedron Lett. 1990, 31, 5487.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1509–1512

1512
T. Kudoh et al.
LETTER
(e) Harrowven, D. C. Tetrahedron Lett. 1991, 32, 3735.
(f) Ogiku, T.; Yoshida, S.; Ohmizu, H.; Iwasaki, T. J. Org.
Chem. 1995, 60, 4585.
NMR (300 MHz, CDCl3): δ = 3.79 (s, 3 H), 4.02 (s, 3 H),
4.08 (s, 3 H), 5.412 (s, 1 H), 5.416 (s, 1 H), 6.05 (d, 1 H, J =
1.7 Hz), 6.11 (d, 1 H, J = 1.7 Hz), 6.82 (dd, 1 H, J = 1.6, 7.7
Hz), 6.85 (d, 1 H, J = 1.6 Hz), 6.93 (s, 1 H), 6.97 (d, 1 H, J
= 7.7 Hz), 8.13 (s, 1 H). 13C NMR (75 MHz, CDCl3): δ =
55.8, 61.1, 61.5, 68.2, 101.2, 102.3, 108.1, 110.5, 114.0,
120.0, 123.4, 128.25, 128.33, 130.4, 138.6, 139.7, 143.1,
147.3, 147.5, 147.6, 153.4, 169.7. IR (KBr): 2940, 1768,
1476, 1227, 1058 cm–1.
(9) (a) Sato, Y.; Tamura, T.; Mori, M. Angew. Chem. Int. Ed.
2004, 43, 2436. (b) Sato, Y.; Tamura, T.; Kinbara, A.; Mori,
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2008, 73, 6932. (f) Foley, P.; Eghbali, N.; Anastas, P. T.
Green Chem. 2010, 12, 888.
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Analytical Data for Phyllamycin A (2)
Mp 231.4–231.3 °C. Rf = 0.63 (3:1 hexane–EtOAc). 1H
NMR (300 MHz, CDCl3): δ = 3.83 (s, 3 H), 3.99 (s, 3 H),
4.10 (s, 3 H), 5.21 (s, 2 H), 6.07 (d, 1 H, J = 1.4 Hz), 6.10 (d,
1 H, J = 1.4 Hz), 6.80–6.83 (m, 2 H), 6.88 (s, 1 H), 6.98 (d,
1 H, J = 8.2 Hz), 8.74 (s, 1 H). 13C NMR (75 MHz, CDCl3):
δ = 55.8, 61.1, 61.6, 69.3, 100.2, 101.4, 108.9, 109.5, 120.5,
120.8, 122.7, 125.5, 129.6, 131.9, 132.9, 139.2, 141.1,
147.7, 148.3, 149.1, 155.6, 171.4. IR (KBr): 2941, 1767,
1482, 1234, 1027 cm–1.
(13) Kudoh, T.; Mori, T.; Shirahama, M.; Yamada, M.; Ishikawa,
T.; Saito, S.; Kobayashi, H. J. Am. Chem. Soc. 2007, 129,
4939.
(14) (a) Sonogashira, K. In Comprehensive Organic Synthesis;
Vol. 3; Trost, B. M.; Fleming, I., Eds.; Pergamon Press:
Oxford, 1991, 521. (b) Bleicher, L.; Cosford, N. D. P. Synlett
1995, 1115.
(15) (a) Lin, M.; Lee, S.; Liu, K. C. S. C. J. Nat. Prod. 1995, 58,
244. (b) Lee, S.; Lin, M.; Liu, C.; Lin, Y.; Liu, K. C. S. C. J.
Nat. Prod. 1996, 59, 1061.
(16) General Procedure for the Intramolecular Anionic
Diels–Alder Reaction of 7a
Analytical Data for Justicidin B (3)
Rf = 0.23 (1:1 hexane–EtOAc). 1H NMR (300 MHz, CDCl3):
δ = 3.82 (s, 3 H), 4.05 (s, 3 H), 5.380 (s, 1 H), 5.384 (s, 1 H),
6.05 (d, 1 H, J = 1.6 Hz), 6.10 (d, 1 H, J = 1.6 Hz), 6.83 (dd,
1 H, J = 8.0, 1.7 Hz), 6.86 (d, 1 H, J = 1.7 Hz), 6.97 (d, 1 H,
J = 8.0 Hz), 7.11 (s, 1 H), 7.19 (s, 1 H), 7.70 (s, 1 H). 13
C
NMR (75 MHz, CDCl3): δ = 55.8, 56.0, 68.0, 101.2, 106.0,
106.1, 108.2, 110.6, 118.2, 118.6, 123.5, 128.5, 128.9,
133.2, 139.5, 139.7, 147.6 × 2, 150.2, 151.9, 169.8. IR
(KBr): 2938, 1754, 1506, 1238, 1158, 1036 cm–1.
Analytical Data for Retrojusticidin B (4)
Mp 224.0–223.5 °C; Rf = 0.40 (1:1 hexane–EtOAc). 1H
NMR (300 MHz, CDCl3): δ = 3.85 (s, 3 H), 4.05 (s, 3 H),
5.21 (s, 2 H), 6.07 (d, 1 H, J = 1.4 Hz), 6.11 (d, 1 H, J = 1.4
Hz), 6.82–6.85 (m, 2 H), 6.99 (d, 1 H, J = 8.5 Hz), 7.09 (s, 1
H), 7.29 (s, 1 H), 8.30 (s, 1 H). 13C NMR (75 MHz, CDCl3):
δ = 55.8, 55.9, 69.3, 101.4, 104.1, 107.7, 108.9, 109.5, 121.4,
122.7, 124.0, 129.7, 129.9, 131.6, 131.9, 137.9, 147.6,
148.3, 150.2, 152.2, 171.3. IR (KBr) 2923, 1751, 1505, 1231
cm–1.
To a solution of 7a (444 mg, 1.08 mmol) in DMSO (6 mL)
was added Triton B (40 wt% in MeOH) (0.6 mL, 120 mol%)
at r.t. The mixture was stirred at r.t. for 24 h. After completed
the reaction, sat. NH4Cl aq solution was added to this and
extracted with hexane–EtOAc (3:1). The combined organic
layers were dried over MgSO4, filtered, and concentrated by
a rotary evaporator. The residue was purified by column
chromatography to afford cycloadduct 8a (408 mg, 92%).
(17) Analytical Data for Phyllamycin C (1)
Mp 193.8–194.3 °C; Rf = 0.57 (1:1 hexane–EtOAc). 1H
Synlett 2013, 24, 1509–1512
© Georg Thieme Verlag Stuttgart · New York

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