Synthesis of two alnustone-like natural diarylheptanoids via 4+3 strategy

Article abstract of DOI:10.1080/00397910802542036

The first total synthesis of (4E,6E)-1,7-bis(3,4-dihydroxyphenyl)-hepta-4, 6-dien-3-one and an alternative synthesis of (4E,6E)-1,7-bis(4-hydroxyphenyl)- hepta-4,6-dien-3-one, two natural diarylheptanoids, mainly based on Claisen-Schmidt condensation were described. The crucial steps of the syntheses were the condensation of OH-protected 4-aryl-2-butanones with OH-protected 3-aryl-acrylaldehydes by the in situ enamination and then deprotection of OH groups to give the corresponding natural diarylheptanoids. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802542036

Synthetic Communications1, 39: 1549–1562, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802542036
Synthesis of Two Alnustone-Like Natural
Diarylheptanoids via 4 þ 3 Strategy
1
2
2
˘
¨
Serdar Burmaoglu, Hu¨lya C¸ elik, Su¨leyman Goksu,
Ahmet Maras¸,2 Ramazan Altundas¸,2 and Hasan Sec¸en2
1Bayburt University, Vocational College, Department of Chemistry,
Bayburt, Turkey
2Ataturk University, Faculty of Arts and Sciences,
¨
Department of Chemistry, Erzurum, Turkey
Abstract: The first total synthesis of (4E,6E)-1,7-bis(3,4-dihydroxyphenyl)-
hepta-4,6-dien-3-one and an alternative synthesis of (4E,6E)-1,7-bis(4-hydroxy-
phenyl)-hepta-4,6-dien-3-one, two natural diarylheptanoids, mainly based on
Claisen–Schmidt condensation were described. The crucial steps of the syntheses
were the condensation of OH-protected 4-aryl-2-butanones with OH-protected
3-aryl-acrylaldehydes by the in situ enamination and then deprotection of OH
groups to give the corresponding natural diarylheptanoids.
Keywords: 1,7-Bis(3,4-dihydroxyphenyl)-hepta-4,6-dien-3-one, 1,7-bis(4-hydro-
xyphenyl)-hepta-4,6-dien-3-one, Claisen–Schmidt condensation, diarylheptanoid,
in situ enamination, synthesis
INTRODUCTION
Diarylheptanoids, which have two aryl rings attached to C-1 and C-7 of a
seven-carbon chain, are a special class of natural products. The first
review of natural diarylheptanoids was published by Cleason et al.,[1]
and they reported the isolation and characterization of approximately
Received August 16, 2008.
Dedicated to Professor Metin Balcı on the occasion of his 60th birthday.
Address correspondence to Hasan Sec¸en, Ataturk University, Faculty of Arts
¨
and Sciences, Department of Chemistry, 25240 Erzurum, Turkey. E-mail: hsecen@
atauni.edu.tr
1549

˘
S. Burmaoglu et al.
1550
Figure 1. Alnustone and alnustone-like natural diarylheptanoids.
120 naturally occurring diarylheptanoids up to 1993. In a second
review,[2] including the literature of 1993–1999, 75 new diarylheptanoids
had been reported for the later 7 years. To our knowledge, after this,
more than 100 new diarylheptanoids were reported in the literature. Stu-
dies have revealed that diarylheptanoids show several biological activities
e.g., anti-inflammatory,[3] antispasmodic,[4] antiemetic,[5] antihepata-
toxic,[6] antiproliferative,[7] and cancer-preventive[8] properties.
Alnustone (1), a nonphenolic natural diarylheptanoid, was reported
to have anti-inflammatory,[9] antihepatotoxic,[6] antiemetic,[5] and anti-
bacterial[10] activities. Three phenolic alnustone-like natural diarylhepta-
noids (2–4) have been reported to have some important biological
activities: 2 with 5-lipoxygenase inhibiting activity[11] and stronger anti-
oxidant activity[12] than L-ascorbic acid and alpha-tocopherol, 3 with
quinone reductase (QR)–inducing activity,[13] and tsaokoarylone (4) with
cytotoxic activity[14] (Fig. 1).
In our previous study, we reported an alternative, efficient, and short
synthesis of alnustone (1) by the condensation of 4-phenyl-2-butanone
and cinnamaldehyde.[15] Moon et al.[14] have recently synthesized
tsaokoarylone (4) based on the base-catalyzed condensation of 4-(4-
hydroxyphenyl)-2-butanone with 3-methoxy-4-hydroxy-cinnamaldehyde.
Xu and Li[16] synthesized 3 by a lithium diisopropylamide (LDA)-
promoted condensation of 4-(4-(methoxymethoxy)phenyl)butan-2-one
with 4-(methoxymethoxy)-cinnamaldehyde. To the best of our knowl-
edge, there is no synthetic report for the preparation of natural diarylhep-
tanoid 2. In this study, we describe the first synthesis of 2 and an
alternative, easy synthesis of 3 based on in situ enamination.
RESULTS AND DISCUSSION
Our synthesis is based on a 4 þ 3 strategy with the condensation of 4-aryl-
2-butanones (which have a four-carbon chain) and cinnamaldehydes
(which have a three-carbon chain). The preparation of 4-aryl-2-
butanones is shown in Scheme 1. For this, methoxymethyl (MOM)-
protected 3,4-dihyroxy-benzaldehyde 5b was condensed with acetone to
give benzalacetone 6, from which benzylacetone 7a was prepared by

Natural Diarylheptanoids
1551
Scheme 1. (i) MOMCl, K2CO3, acetone, reflux, 2.5 h, 70%; (ii) acetone, 10%
NaOH, rt, 3 h, 91%; (iii) H2 (gas), Pd-C (cat.), 12 h, 79%; (iv) Ac2O-pyridine,
0 ꢀC ! 25 ꢀC, 20 h, 80%.
Pd-C-catalyzed hydrogenation. On the other hand, commercially avail-
able 4-(4-hydroxyphenyl)butan-2-one (7b) was converted to the corre-
sponding acetate derivative 7c by acetylation with Ac2O-pyridine.
For the preparation of cinnamaldehydes 12a and b, we used commer-
cially available cinnamic acids 8a and b as starting materials. Acid-
catalyzed esterification of the acids 8a and b with methanol (MeOH) gave
the ester derivatives 9a and b. Protections of OH groups in 9a and b were
performed in two different ways. While MOM protection of 9a gave 10a,
tetrahydropyranyl (THP) protection of 9b afforded 10b. The reduction of
the cinnamic esters 10a and b with LiAlH4 gave cinnamyl alcohols 11a
and b. The oxidation of the cinnamyl alcohols 11a and b with active
MnO2 afforded cinnamaldehydes 12a and b (Scheme 2).
Scheme 2. (i) MeOH, p-TsOH (cat.), reflux, 24 h, 9a: 84%, 9b: 92%; (ii) 10a:
MOMCl, acetone, reflux, 1 h, 75%; 10b: DHP, CF3COOH (cat.), CH2Cl2, 48 h,
90%; (iii) 11a: LiAlH4, Et2O, 0ꢀC ! 25ꢀC, 4 h, then H2O, 66%; 11b: LiAlH4,
Et2O 0 ꢀC ! 25 ꢀC, 13 h, then H2O, 80%. (iv) 12a: MnO2, CH2Cl2, 10 h, 44%;
12b: MnO2, acetone, 10 h, 82%.

˘
S. Burmaoglu et al.
1552
Scheme 3. (i) Pyrrolidine, AcOH, Et2O, 0 ꢀC ! 25 ꢀC, 12 h, then 0.1 M HCl, 13:
73%; (ii) 1M HCl, ether, 50 ꢀC, 1h, 95% (iii) MeOH, p-TsOH (cat.), reflux, 20 h,
59% via 12b.
The most critical step of the synthesis was the condensation of buta-
noids 7a and c and cinnamaldehydes 12a and b to give diarylheptanoids.
Baranovsky et al.[17] synthesized alnustone-like diarylheptanoids via a
4 þ 3 strategy based on LDA-promoted aldol condensations of 4-aryl-
2-butanones and 3-aryl-acrylaldehydes. However, this method includes
a two-step reaction: (i) addition of enolate prepared from 4-aryl-2-
butanones to 3-aryl-acrylaldehydes to give beta-hydroxyketones and (ii)
acid-catalyzed elimination of water. Itokawa et al.[18] reported a succes-
sive method in one step for the condensation of 6-aryl-2-hexanone and
benzaldehydes to give 1,7-diaryl-1-hepten-3-ones. This method includes
a condensation based on in situ enamination using pyrrolidine and
AcOH. In our previous study,[15] we successively used the latter method
for the synthesis of alnustone by the condensation of benzylacetone
and cinnamaldehyde. Therefore, in the present study, we preferred the
same method for the condensation of 4-aryl-2-butanones 7a and c and
cinnamaldehydes 12a and b. Our results are shown in Scheme 3.
The condensation of MOM-protected 7a and 12a gave diarylhepta-
noid derivative 13 from which the natural diarylheptanoid 2 was easily
obtained by treatment with 1 M HCl. However, the condensation of
the acetylated butanoid 7c and THP-protected cinnamaldehyde 12b gave
a mixture of 14a–c. Because all groups attached to oxygen atoms may be
easily removed, the mixture of 14a–c was subjected to trans-esterification
to give the natural product 3 itself.
CONCLUSION
In this article, we described the first synthesis of natural diarylheptanoid
2 and an alternative, easy synthesis of natural product 3. We showed

Natural Diarylheptanoids
1553
again that in situ enamination can be used for the preparation of
alnustone-like diarylheptanoids in the presence of sensitive protective
groups such as MOM or THP.
EXPERIMENTAL
General Information
Column chromatography (CC) used silica gel 60 (70–230 mesh). Thin-
layer chromatography (TLC) used aluminum-backed silica-gel 60 F254
plates (Merck). Solvents were purified and dried by standard procedures
before use. Melting points were measured with a Buchi-539 cap. melting-
¨
point apparatus and are uncorrected. 1H and 13C NMR spectra at 400 or
100 MHz, 200 or 50 MHz, were determined on Varian spectrometer (d in
ppm, J in Hz). Carbon and hydrogen assignments were made by compar-
ison of similar structures: Interchangeable protons and carbons were
marked with the same letter (i.e.,a,b,c). Electron-impact ionization–mass
spectrometry (EI-MS) was measured on a Thermo-Finnigan mass analy-
zer in m=z (rel. int., %). Elemental analyses were carried out with a Leco
CHNS-932 instrument.
3,4-Bis(methoxymethoxy)benzaldehyde (5b)
K2CO3 (2.00 g, 14.5 mmol) and methoxymethyl chloride (1.170 g, 1.1 mL,
14.5 mmol) were added to a solution of 3,4-dihydroxybenzaldehyde (5a)
(0.500 g, 3.6 mmol) in acetone (40 mL). The mixture was refluxed for
2.5 h. The precipitate was filtered and dispatched. The solvent was
removed under reduced pressure. The residue was dissolved in CH2Cl2
(30 mL), washed with water (3 ꢁ 10 mL), and dried (Na2SO4). The
evaporation of the solvent gave 5b as a brown oil (0.57 g, 70%).
1H NMR (200 MHz, CDCl3) d 9.86 (s, 1H, CHO); 7.47 (d, 1H, H-2,
J2,6 ¼ 1.5 Hz); 7.41 (dd, 1H, H-6, J5,6 ¼ 8.2 Hz, J2,6 ¼ 1.5 Hz); 7.23 (d, 1H,
H-5, J5,6 ¼ 8.2 Hz); 5.32 (s, 4H, 2 ꢁ OCH2O); 3.53 (s, 6H, 2 ꢁ OCH3);
1H NMR spectrum is in agreement with data given in the literature.[19]
(E)-4-(3,4-Bis(methoxymethoxy)phenyl)but-3-en-2-one (6)[20]
3,4-Bis(methoxymethoxy)benzaldehyde (5b) (0.500 g, 2.21 mmol) was dis-
solved in acetone (0.165 mL, 0.130 g, 2.24 mmol). To this solution, 25 mL
10% NaOH was added. While the mixture was being magnetically stirred

˘
S. Burmaoglu et al.
1554
at rt for 3 h, progress of the reaction was monitored by TLC. The organic
phase was extracted with benzene and dried (Na2SO4). The evaporation
of the solvent under reduced pressure gave 6 as a brown oil (0.540 g,
91%).
1H NMR (400 MHz, CDCl3) d 7.43 (d, 1H, H-4, J3,4 ¼ 16.3 Hz); 7.37
(bs, 1H, H-20); 7.16 (m, as quasi bs, 2H, H-50 and H-60); 6.66 (d, 1H, H-3,
J3,4 ¼ 16.3 Hz); 5.27 (s, 2H, OCH2O); 5.25 (s, 2H, OCH2O); 3.52 (s, 3H,
OCH3); 3.51 (s, 3H, OCH3); 2.35 (s, 3H, [C(O)CH3]. 13C NMR (100 MHz,
a
a
CDCl3) 198.5 (C-2); 149.6 (C-40 ); 147.7 (C-30 ); 143.3 (C-4); 129.1 (C-10);
b
b
126.2 (C-60); 123.9 (C-3); 116.5 (C-50 ); 116.0 (C-20 ); 95.7 (OCH2O); 95.3
(OCH2O); 56.5 (2C, 2 ꢁ OCH3); 27.6 (C-1).
4-(3,4-Bis(methoxymethoxy)phenyl)butan-2-one (7a)[20]
Pd–C (50 mg) and benzalacetone 6 (0.500 g, 1.88 mmol) in EtOAc (50 mL)
were placed into a 100-mL flask. A balloon filled with H2 gas (3 L) was
fitted to the flask. The mixture was deoxygenated by flushing with H2
and then hydrogenated at rt for 12 h. The catalyst was removed by filtra-
tion.The evaporation of the solvent under reduced pressure gave 7a as a
brown oil (0.400 g, 79%).
1
H NMR (400 MHz, CDCl3) d 7.01 (d, 1H, H-50, J5 ,6 ¼ 8.4 Hz); 6.94 (d,
0
0
1H, H-20, J2 ,6 ¼ 2.2 Hz); 6.72 (dd, 1H, H-6 , J5 ,6 ¼ 8.4 Hz, J2 ,6 ¼ 2.2 Hz);
5.17 (s, 2H, OCH2O); 5.15 (s, 2H, OCH2O); 3.47 (s, 3H, OCH3); 3.46 (s, 3H,
OCH3); 2.78 (A2 part of A2B2 system, m, 2H, 2 ꢁ H-3a); 2.69 (B2 part of
A2B2 system, m, 2H, 2 ꢁ H-4a); 2.09 (s, 3H, CH3). 13C NMR (100MHz,
0
0
0
0
0
0
0
a
a
CDCl3) d 208.1 (C-2); 147.5 (C-30 ); 145.7 (C-40 ); 135.7 (C-10); 122.3
b
b
(C-60); 117.2 (C-20 ); 117.1 (C-50 ); 95.8 (OCH2O); 95.7 (OCH2O); 56.4
(OCH3); 56.3 (OCH3); 45.4 (C-3); 30.2 (C-4); 29.4 (C-1).
4-(4-Acetoxyphenyl)butan-2-one (7c)[21]
4-(4-Hydroxyphenyl) butan-2-one (7b) (1.000 g, 6.09 mmol) and Ac2O
(0.920 g, 9.11 mmol) were placed into a 100-mL flask. The solution was
cooled to 0ꢀC, and pyridine (1 mL) was added. The mixture was stirred
at rt for 20 h. The reaction mixture was cooled to 0ꢀC, and 1 M HCl
(20 mL) was added. The organic phase was extracted with CH2Cl2
(2 ꢁ 25 mL), washed with saturated NaHCO3 (2 ꢁ 10 mL) and dried
(Na2SO4). The evaporation of the solvent under reduced pressure gave
7c as a yellow oil (1.000 g; 80%).
1H NMR (200 MHz, CDCl3) d 7.22–7.18 (AA0 part of AA0XX0 sys-
tem, m, 2H, H-20=60); 7.03–6.99 (XX0 part of AA0XX0 system, m, 2H,

Natural Diarylheptanoids
1555
H-30=50); 2.94–2.73 (A2B2 system, m, 4H, 2 ꢁ H-3 and 2 ꢁ H-4); 2.26
(s, 3H, CH3); 2.15 (s, 3H, CH3). 13C NMR (50 MHz, CDCl3) d 207.7
(C-2); 169.2 (CO of ester); 148.7 (C-40); 138.2 (C-10); 129.0 (C-20=60);
121.2 (C-30=50); 44.7 (C-3); 31.9 (C-4); 29.7 (C-1); 20.8 (CH3 of acetate).
(E)-Methyl 3-(3,4-dihydroxyphenyl)acrylate (9a)
Fifty mg of p-TsOH was added to a solution of caffeic acid (8a) (1.88 g,
10.4 mmol) in 50 mL of MeOH. The mixture was refluxed for 24 h. The
excess of MeOH was evaporated under reduced pressure. The residue
was dissolved in EtOAc (50 mL), washed with saturated Na2CO3
(3 ꢁ 5 mL), and dried (Na2SO4). The evaporation of the solvent gave ester
9a as a yellow solid (1.700 g, 84%). Mp 156–158ꢀC. Lit.[22] mp 152–153ꢀC;
lit.[23] mp 158ꢀC.
1H NMR (200 MHz, CDCl3) d 7.55 (d, 1H, H-3, J2,3 ¼ 15.9 Hz); 7.04
(d, 1H, H-20, J2 ,6 ¼ 2.2 Hz) 6.95 (dd, 1H, H-60, J5 ,6 ¼ 8.1 Hz;
0
0
0
0
0
0
0
0
0
J2 ,6 ¼ 2.2 Hz); 6.78 (d, 1H, H-5 , J5 ,6 ¼ 8.1 Hz); 6.26 (d, 1H, H-2,
1
J2,3 ¼ 15.9 Hz); 4.93 (bs, 2H, 2 ArOH) 3.75 (s, 3H, OCH3). H NMR
spectrum is in agreement with data given in the literature.[23]
(E)-Methyl 3-(4-Hydroxyphenyl)acrylate (9b)
The procedure described previously for the synthesis of 9a was applied to
(4-hydroxyphenyl)acrylic acid 8b in MeOH to give 9b in a yield of 92%.
Colorless solid. Mp 136–137ꢀC. Lit.[24] mp 138–139ꢀC.
1H NMR (200 MHz, CDCl3) d 7.65 (d, 1H, H-3, J2,3 ¼ 16.0 Hz); 7.44–
7.40 (AA0 part of AA0XX0 system, quasi d, 2H, H-20=60, J ¼ 8.6 Hz); 6.90–
6.86 (XX0 part of AA0XX0 system, quasi d, 2H, H-30=50, J ¼ 8.6 Hz); 6.30
(d, 1H, H-2, J2,3 ¼ 16.0 Hz); 3.82 (s, 3H, OCH3). 13C NMR (50 MHz,
CDCl3) d 168.1 (C-1); 158.1 (C-40); 145.1 (C-3); 130.1 (C-20=60); 127.1
(C-10); 116.0 (C-30=50); 115.0 (C-2); 51.8 (OCH3). 1H NMR and 13C NMR
spectra are in agreement with data given in the literature.[24]
(E)-Methyl 3-(3,4-Bis(methoxymethoxy)phenyl)acrylate (10a)
K2CO3 (3.56 g, 25.7 mmol) and methoxymethyl chloride (2.070 g,
1.95 mL, 25.7 mmol) were added to a solution of methyl caffeate (9a)
(1.00 g, 5.15 mmol) in acetone (40 mL). The mixture was refluxed for
1 h. The precipitate was filtered and dispatched. The solvent was removed
under reduced pressure. Chromatography of the crude product on a

˘
S. Burmaoglu et al.
1556
silica-gel column (30 g) eluting with 3:7 EtOAc=hexane gave 10a as a
yellow oil (1.090 g, 75%).
1H NMR (400MHz, CDCl3) d 7.61 (d, 1H, H-3, J2,3 ¼ 16.1 Hz); 7.35
0
(d, 1H, H-20, J2 ,6 ¼ 1.5 Hz); 7.15 (d, 1H, H-5 , J5 ,6 ¼ 8.6 Hz); 7.13 (dd,
0
0
0
0
1H, H-60, J5 ,6 ¼ 8.6 Hz, J2 ,6 ¼ 1.5 Hz); 6.32 (d, 1H, H-2, J2,3 ¼ 16.1 Hz);
5.26 (s, 2H, OCH2O); 5.24 (s, 2H, OCH2O); 3.79 (s, 3H, OCH3 of ester);
3.52 (s, 3H, OCH3); 3.50 (s, 3H, OCH3). 13C NMR (100 MHz, CDCl3) d
0
0
0
0
a
a
167.8 (C-1); 149.4 (C-30 ); 147.6 (C-40 ); 144.6 (C-3); 129.0 (C-10); 123.6
(C-60); 116.5 (C-50 ); 116.3 (C-20 ); 115.8 (C-2b); 95.7 (OCH2O); 95.3
(OCH2O); 56.5 (2C, 2 ꢁ OCH3); 51.8 (OCH3 of ester). 1H NMR spectrum
is in agreement with data given in the literature.[22]
b
b
(E)-Methyl 3-(4-(tetrahydro-2 H-pyran-2-yloxy)phenyl) Acrylate (10b)
3,4-Dihydro-2H-pyran (3.000 g, 35.7 mmol) was added to a solution of
acrylic ester 9b (4.00 g, 22.5 mmol) in CH2Cl2 (20 mL). The mixture was
cooled to 0ꢀC, and five drops of CF3COOH were added. The resulting
mixture was magnetically stirred at rt for 48 h. The mixture was washed
with brine (2 ꢁ 10 mL) and dried (MgSO4). After the evaporation of the
solvent, recystallization of the crude product from CH2Cl2–hexane gave
10b as a yellow solid (5.300 g, 90%). Mp 64–65ꢀC.
1H NMR (400 MHz, CDCl3) d 7.62 (d, 1H, H-3, J ¼ 16.0 Hz);
7.43–7.40 (AA0 part of AA0XX0 system, d, 2H, H-20=60, J ¼ 8.8 Hz);
7.02–6.99 (XX0 part of AA0XX0 system, d, 2H, H-30=50, J ¼ 8.8 Hz); 6.28
(d, 1H, H-2, J2,3 ¼ 16.0 Hz); 5.43 (t, 1H, H-200, J ¼ 3.1 Hz); 3.82 (ddd, A part
of AB system, 1H, H-600, J ¼ 12.1 Hz, J ¼ 9.5 Hz, J ¼ 2.9 Hz); 3.75 (s, 3H,
OCH3); 3.58 (dddd, B part of AB system, 1H, H-600, J ¼ 12.1 Hz, J ¼ 3.9 Hz,
J ¼ 3.9 Hz, J ¼ 1.1 Hz); 2.00–1.92 (m, 1H); 1.85–1.81 (m, 2H); 1.79–1.51 (m,
13
3H). C NMR (50 MHz, CDCl3) d 167.6 (C-1); 158.9 (C-40); 144.5 (C-3);
129.5 (C-20=60); 127.9 (C-10); 116.7 (C-30=50); 115.6 (C-2); 96.2 (C-200);
62.0 (C-600); 51.5 (OCH3); 30.2 (C-300); 25.1 (C-500); 18.6 (C-400). Anal. calcd
for C15H18O4 (262.3); C, 68.68; H, 6.92. Found: C, 68.74; H, 7.07.
(E)-3-(3,4-Bis(methoxymethoxy)phenyl)prop-2-en-1-ol (11a)
A solution of acrylic ester 10a (0.690 g, 2.45 mmol) in Et2O (10 mL) was
added dropwise to a slurry of LiAlH4 (0.046 g, 1.23 mmol) in dry Et2O
(10 mL) at 0ꢀC. While the mixture was magnetically stirred at rt, progress
of the reaction was monitored by TLC. After completion of the reaction
(4 h), the mixture was cooled to 0ꢀC, and 2 mL of H2O were added. The
precipitate was filtered and dispatched. EtOAc (30 mL) and H2O (10 mL)

Natural Diarylheptanoids
1557
were added to this mixture. The organic phase was separated and dried
(MgSO4). Removal of the solvent gave the cinnamyl alcohol 11a as a
brownish oil (0.412 g, 66%).
1
H NMR (400 MHz, CDCl3) d 7.22 (d, 1H, H-20, J2 ,6 ¼ 2.2 Hz); 7.10
0
00
(d, 1H, H-50, J5 ,6 ¼ 8.4 Hz); 6.97 (dd, 1H, H-6 , J5 ,6 ¼ 8.4 Hz,
0
0
0
0
0
0
J2 ,6 ¼ 2.2 Hz); 6.53 (bd, 1H, H-3, J2,3 ¼ 15.9 Hz); 6.26 (dt, 1H, H-2,
J2,3 ¼ 15.9 Hz, J1,2 ¼ 5.7 Hz); 5.24 (s, 2H, OCH2O); 5.23 (s, 2H, OCH2O);
4.29 (d, 2H, 2 ꢁ H-1, J1,2 ¼ 5.7 Hz); 3.52 (s, 3H, OCH3); 3.51 (s, 3H,
13
a
a
OCH3). C NMR (100 MHz, CDCl3) d 147.6 (C-30 ); 147.1 (C-40 );
b
131.8 (C-10); 130.6 (C-3); 127.8 (C-2); 121.2 (C-60); 116.9 (C-20 ); 114.8
b
(C-50 ); 95.7 (OCH2O); 95.6 (OCH2O); 63.7 (C-1); 56.4 (2C, 2 ꢁ OCH3).
1H NMR spectrum is in agreement with data given in the literature.[22]
(E)-3-(4-(tetrahydro-2 H-pyran-2-yloxy)phenyl)prop-2-en-1-ol (11b)[25]
The procedure described previously for the synthesis of 11a was applied
to ester 10b to give yellow oil 11b (80%).
1H NMR (400 MHz, CDCl3) d 7.27–7.23 (AA0 part of AA0XX0
system, d, 2H, H-20 and H-60, J ¼ 8.8 Hz); 6.98–6.94 (XX0 part of AA0XX0
system, d, 2H, H-30 and H-50, J ¼ 8.8 Hz); 6.49 (A part of AB system, d,
1H, H-3, J2,3 ¼ 15.7 Hz); 6.18 (B part of AB system, dt, 1H, H-2,
J2,3 ¼ 15.7 Hz, J1,2 ¼ 5.9 Hz); 5.38 (t, 1H, H-200, J ¼ 3.3 Hz); 4.22 (t, 2H,
2 ꢁ H-1, J1,2 ¼ 5.9 Hz); 3.87 (ddd, A part of AB system, 1H, H-600, J ¼
12.6 Hz, J ¼ 9.9 Hz, J ¼ 3.3 Hz); 3.57 (dt, B part of AB system, 1H, H-600,
J ¼ 12.6 Hz, J ¼ 3.9 Hz); 2.61 (bs, 1H, OH); 1.99–1.55 (m, 6H, 2 ꢁ H-300,
13
2 ꢁ H-400, 2 ꢁ H-500). C NMR (100MHz, CDCl3) d 156.4 (C-40); 130.4
(C-2); 130.2 (C-10); 127.3 (C-20=60); 126.6 (C-3); 116.3 (C-30=50); 96.1
(C-200); 63.4 (C-1); 61.8 (C-600); 30.1 (C-300); 25.0 (C-500); 18.6 (C-400). Anal.
calcd. for C14H18O3 (234.29): C, 71.77; H, 7.74. Found: C, 71.84; H, 7.78.
(E)-3-(3,4-Bis(methoxymethoxy)phenyl)acrylaldehyde (12a)[26]
Freshly prepared MnO2 (0.420 g) was added to a solution of 11a (0.690 g,
2.74 mmol) in CH2Cl2 (40 mL). The mixture was magnetically stirred at rt
for 10 h. The mixture was filtered, and the precipitate was dispatched.
After the removal of the solvent, the chromatography of the residue on
a silica-gel column eluting with 2:1 EtOAc–hexane gave 12a as a brown
oil (0.306 g, 44%).
1H NMR (400 MHz, CDCl3) d 9.63 (d, 1H, H-1; J1,2 ¼ 7.7 Hz); 7.38
(d, 1H, H-3, J2,3 ¼ 15.8 Hz); 7.38 (bs, 1H, H-20); 7.18 (m, 2H, H-50 and
H-60); 6.60 (dd, 1H, H-2, J2,3 ¼ 15.8 Hz, J1,2 ¼ 7.7 Hz); 5.27 (s, 2H,

˘
S. Burmaoglu et al.
1558
OCH2O); 5.24 (s, 2H, OCH2O); 3.51 (s, 3H, OCH3); 3.50 (s, 3H, OCH3).
a
13C NMR (100 MHz, CDCl3) d 193.8 (C-1); 152.7 (C-3); 150.2 (C-30 );
a
b
147.7 (C-40 ); 128.7 (C-10); 127.6 (C-2); 124.2 (C-60); 116.4 (C-50 ); 116.3
b
(C-20 ); 95.8 (OCH2O); 95.3 (OCH2O); 56.6 (OCH3); 56.5 (OCH3).
(E)-3-(4-(Tetrahydro-2 H-pyran-2yloxy) Phenyl)acryl Aldehyde (12b)
Freshly prepared MnO2 (3.70 g, 42.5 mmol) was added to a solution of
11b (1.000 g, 4.27 mmol) in dry acetone (30 mL). The mixture was magne-
tically stirred at rt for 10 h. The mixture was filtered, and the precipitate
was dispatched. The evaporation of the solvent gave 12b as yellow solid
(0.810 g, 82%). Mp 96–98ꢀC (CH2Cl2–hexane). Lit.[25] mp 65–67ꢀC.
1H NMR (400 MHz, CDCl3) d 9.64 (d, 1H, H-1, J1,2 ¼ 7.7 Hz); 7.50
(AA0 part of AA0XX0 system, d, 2H, H-20=60, J ¼ 8.8Hz); 7.41 (d, 1H,
H-3, J2,3 ¼ 15.7Hz); 7.08 (XX0 part of AA0XX0 system, d, 2H, H-30=50,
J¼ 8.8 Hz); 6.60 (dd, 1H, H-2, J2,3 ¼ 15.7 Hz, J1,2 ¼ 7.7 Hz); 5.48 (t, 1H,
H-200, J ¼ 3.1 Hz); 3.84 (A part of AB system, ddd, 1H, H-600, J ¼ 11.9 Hz,
J¼ 11.3 Hz, J ¼ 3.0 Hz); 3.61 (B part of AB system, dddd, 1H, H-600,
J¼ 11.9 Hz, J¼ 3.6 Hz, J ¼ 3.6 Hz, J¼ 1.1 Hz); 2.02–1.58 (m, 6H, 2ꢁ H-300,
00, 2 ꢁ H-400, 2ꢁ H-500). 13C NMR (100 MHz, CDCl3) d 193.7 (C-1); 159.6 (C-
40); 152.7 (C-3); 130.3 (C-20=60); 127.3 (C-10); 126.6 (C-2); 116.8 (C-30=50);
96.0 (C-200); 62.0 (C-600); 30.0 (C-300); 25.0 (C-500); 18.4 (C-400). Anal. calcd.
for C14H16O3 (232.28): C, 72.39; H, 6.94. Found: C, 72.35; H, 7.02.
(4E,6E)-1,7-Bis(3,4-bis(methoxymethoxy)phenyl)hepta-4,6-dien-3-one (13)
A solution of 7a (0.110 g, 0.41 mmol) in dry ether (10 mL) was cooled to
0ꢀC. While the solution was being magnetically stirred at the same tem-
perature, a solution of pyrrolidine (0.015 g, 0.22 mmol) in ether (1 mL)
and then AcOH (0.015 g, 0.25 mmol) in dry ether (1 mL) were added.
The mixture was stirred at the same temperature for 30 min. A solution
of acrylaldehyde 12a (0.080 g, 0.32 mmol) in ether (5 mL) was added
dropwise to the mixture, and the resulting mixture was stirred at rt for
12 h. Five mL of 0.1 M HCl were added to the mixture. The organic
phase was extracted with Et2O (2 ꢁ 10 mL) and dried (Na2SO4). Evapora-
tion of the solvent and chromatography of the residue on a silica-gel
column (20 g) eluting with 7:3 hexane–EtOAc gave 13 as a yellow oil
(0.116 g, 73%).
1H NMR (400 MHz, CDCl3) d 7.30 (dd, 1H, H-5, J4,5 ¼ 15.4 Hz,
J5,6 ¼ 10.6 Hz), 7.29 (d, 1H, H-200, J2 ,6 ¼ 2.2 Hz); 7.12 (A part of AB
00 00
system, d, 1H, H-500, J5 ,6 ¼ 8.8 Hz); 7.05 (B part of AB system, d, 1H,
00 00

Natural Diarylheptanoids
1559
0
H-600, J5 ,6 ¼ 8.8 Hz); 7.04 (A part of AB system, d, 1H, H-5 ,
00 00
0
0
0
0
0
J5 ,6 ¼ 8.4 Hz); 7.01 (d, 1H, H-2 , J2 ,6 ¼ 2.2 Hz); 6.85 (A part of AB sys-
tem, d, 1H, H-7, J6,7 ¼ 15.4 Hz); 6.79 (B part of AB system, dd, 1H, H-60,
0
0
0
0
J5 ,6 ¼ 8.4 Hz, J2 ,6 ¼ 2.2 Hz); 6.74 (B part of AB system, dd, 1H, H-6,
J6,7 ¼ 15.4 Hz, J5,6 ¼ 10.6 Hz); 6.26 (d, 1H, H-4, J4,5 ¼ 15.4 Hz); 5.25 (s,
2H, OCH2O); 5.24 (s, 2H, OCH2O); 5.21 (s, 2H, OCH2O); 5.19 (s, 2H,
OCH2O); 3.53 (s, 3H, OCH3); 3.51 (s, 3H, OCH3); 3.50 (s, 3H, OCH3);
3.50 (s, 3H, OCH3); 2.90–2.85 (A2B2 system, m, 4H, 2 ꢀ H-1 and
13
2 ꢀ H-2). C NMR (100 MHz, CDCl3) d 199.6 (C-3); 148.5 (C-400);
147.7 (C-300); 147.5 (C-30); 145.8 (C-40); 143.2 (C-5); 141.3 (C-7); 136.1
a
(C-10); 130.9 (C-100); 129.0 (C-4); 125.7 (C-6); 122.6 (C-600 ); 122.4
a
b
b
b
b
(C-60 ); 117.2 (2C, C-500 and C-20 ); 116.6 (C-50 ); 115.0 (C-200 ); 96.3
(OCH2O); 95.8 (OCH2O); 95.7 (OCH2O); 95.7 (OCH2O); 56.5 (2C,
2 ꢀ OCH3); 56.4 (OCH3); 56.3 (OCH3); 42.7 (C-2); 30.0 (C-1).
(4E,6E)-1,7-Bis(3,4-dihydroxyphenyl)hepta-4,6-dien-3-one (2)
To a solution of 13 (0.116 g, 0.23 mmol) in ether (5 mL), 1 M HCl (2 mL)
was added. The mixture was stirred at 50ꢁC for 1 h. Ten mL of ether were
added. The organic phase was separated, washed with water (2 ꢀ 2 mL),
and dried (Na2SO4). Removal of the solvent and filtration of the residue
on a short silica-gel column (2 g) gave 2 as yellow oil (0.071 g, 95%).
1H NMR (400 MHz, CD3OD) d 7.36 (dd, 1H, H-5, J4,5 ¼ 15.4 Hz,
J5,6 ¼ 10.8 Hz), 6.98 (d, 1H, H-200, J2 ,6 ¼ 2.0 Hz), 6.89 (A part of AB sys-
00 00
tem, d, 1H, H-7, J6,7 ¼ 15.7 Hz); 6.87 (A part of AB system, dd, 1H, H-600,
00 00
00 00
J5 ,6 ¼ 8.3 Hz, J2 ,6 ¼ 2.0 Hz); 6.76 (B part of AB system, dd, 1H, H-6,
J6,7 ¼ 15.7 Hz, J5,6 ¼ 10.8 Hz); 6.74 (B part of AB system, d, 1H, H-500,
0
00 00
0
0
J5 ,6 ¼ 8.3 Hz); 6.66 (A part of AB system, d, 1H, H-5 , J5 ,6 ¼ 8.1 Hz);
6.64 (d, 1H, H-20, J2 ,6 ¼ 2.0 Hz); 6.52 (B part of AB system, dd, 1H,
0
0
H-60, J5 ,6 ¼ 8.1 Hz, J2 ,6 ¼ 2.0 Hz); 6.22 (d, 1H, H-4, J4,5 ¼ 15.4 Hz),
2.89–2.73 (A2B2 system, m, 4H, 2 ꢀ H-1 and 2 ꢀ H-2). 13C NMR
(100 MHz, CD3OD) d 201.8 (C-3); 147.3 (C-400); 145.5 (C-300); 145.0 (C-
30); 143.3 (C-40); 143.3 (C-5) 142.8 (C-7); 132.9 (C-10); 128.6 (C-100);
127.6 (C-4); 123.8 (C-6); 120.7 (C-600); 119.4 (C-60); 115.3 (C-500); 115.3
0
0
0
0
1
(C-20); 115.2 (C-50); 113.4 (C-200); 42.0 (C-2); 30.0 (C-1). H NMR and
13C NMR spectra are in agreement with data given in the literature.[12]
(4E,6E)-1,7-Bis(4-hydroxyphenyl)hepta-4,6-dien-3-one (3)
The condensation of 4-(4-acetoxyphenyl)-butan-2-one (7c) (0.300 g, 1.45
mmol) and (E)-3-(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)acrylaldehyde

˘
S. Burmaoglu et al.
1560
(12b) (0.320 g, 1.38 mmol) via the procedure described previously gave a
mixture of 14a–c. Without separation, the mixture was dissolved in
MeOH (40 mL), and 0.060 g of p-TsOH was added. The resulting mixture
was refluxed for 20 h. After the removal of MeOH under reduced pres-
sure, CH2Cl2 (50 mL) was added, and the organic phase was washed with
saturated NaHCO3 and dried (Na2SO4). Removal of the solvent, and
TLC on a silica-gel plate, eluting with CHCl3–MeOH–H2O (90:10:1) gave
3 as yellow oil (0.250 g, 59%).
1H NMR (400 MHz, acetone-d6) d 7.44 (AA0 part of AA0XX0 system,
d, 2H, H-20 and H-60, J ¼ 8.4 Hz); 7.38 (dd, 1H, H-5, J5,6 ¼ 10.6 Hz,
J4,5 ¼ 15.4 Hz); 7.07 (AA0 part of AA0XX0 system, d, 2H, H-200 and
H-600, J ¼ 8.4 Hz); 7.01 (A part of AB system, d, 1H, H-7, J6,7 ¼ 15.4 Hz);
6.88 (B part of AB system, dd, H-6, J6,7 ¼ 15.4 Hz, J5,6 ¼ 10.6 Hz); 6.86
(XX0 part of AA0XX0 system, d, 2H, H-300 and H-500, J ¼ 8.4 Hz); 6.74
(XX0 part of AA0XX0 system, d, 2H, H-30 and H-50, J ¼ 8.4 Hz); 6.25
(d, 1H, H-4, J ¼ 15.4 Hz); 2.90–2.78 (A2B2 system, m, 4H, 2 ꢁ H-1 and
13
2 ꢁ H-2). C NMR (100 MHz, acetone-d6) d 198.6 (C-3); 159.1 (C-400);
155.8 (C-40) 143.2 (C-5); 141.4 (C-7); 132.5 (C-10); 129.5 (C-20 and C-60);
129.2 (C-200 and C-600); 128.6 (C-4); 128.2 (C-100); 124.3 (C-6); 116.0
1
(C-300 and C-500); 115.3 (C-30 and C-50); 42.2 (C-2); 29.5 (C-1). H NMR
and 13C NMR spectra are in agreement with data given in the literature.[27]
ACKNOWLEDGMENTS
We thank the Scientific and Technological Research Council of Turkey
(TBAG-105T168) and Ataturk University for financial support of this
¨
work, Dr. Ebru Mete for elemental analysis, and Bilal Altundas for
linguistic corrections.
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