Synthesis of new biosynthetically important diarylheptanoids and their oxa- and fluoro-analogues by three different strategies

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Synthesis of New Biosynthetically Important

Diarylheptanoids and Their Oxa- and Fluoro- Analogues

by Three Different Strategies

Alexander Baranovsky ^{a b}, Bettina Schmitt ^{a c}, Daniel J. Fowler ^a& Bernd Schneider ^a

^aMax-Planck Institute for Chemical Ecology, Jena, Germany

^bInstitute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Minsk, Belarus

^cCombinature Biopharm AG, Berlin, Germany

Published online: 17 Aug 2006.

To cite this article: Alexander Baranovsky , Bettina Schmitt , Daniel J. Fowler & Bernd Schneider (2003): Synthesis of New

Biosynthetically Important Diarylheptanoids and Their Oxa- and Fluoro- Analogues by Three Different Strategies, Synthetic

Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:6, 1019-1045

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SYNTHETIC COMMUNICATIONS^Õ

Vol. 33, No. 6, pp. 1019–1045, 2003

Synthesis of New Biosynthetically Important

Diarylheptanoids and Their Oxa- and Fluoro-

Analogues by Three Diﬀerent Strategies

Alexander Baranovsky,^#Bettina Schmitt,^yDaniel J. Fowler,

*

and Bernd Schneider

Max-Planck Institute for Chemical Ecology, Jena,

Germany

ABSTRACT

Wittig, aldol and Wittig-Horner reactions have been used to synthe-

size new diarylheptanoids, which are putative intermediates in

phenylphenalenone biosynthesis in plants. The Wittig-Horner

approach was most suitable and gave signiﬁcantly higher yields in

comparison with other methods.

^#Current address: Institute of Bioorganic Chemistry, National Academy of

Sciences of Belarus, Minsk, Belarus.

^yCurrent address: Combinature Biopharm AG, Berlin, Germany.

*

Correspondence: Bernd Schneider, Max-Planck Institute for Chemical

Ecology, Beutenberg Campus, Winzerlaer Str. 10, 07745 Jena, Germany;

Fax: þ49-3641-571601; E-mail: schneider@ice.mpg.de.

1019

DOI: 10.1081/SCC-120016367

Copyright & 2003 by Marcel Dekker, Inc.

0039-7911 (Print); 1532-2432 (Online)

www.dekker.com

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Baranovsky et al.

Key Words: Diarylheptanoids; Aldol reaction; Wittig reaction;

Wittig-Horner reaction.

1. INTRODUCTION

Diarylheptanoids represent a group of natural products occurring in

various monocot and dicot plant species.^[1,2]The Zingiberaceae plant

family is an especially rich source of diarylheptanoids. Curcumin, the

most well-known diarylheptanoid, is a major spice and pigment principle

of Curcuma longa (Zingiberaceae) and other Curcuma species. In bioas-

says it exhibits strong antioxidant and chemopreventive activities.^[3,4]

Diarylheptanoids of the Zingiberaceae structurally related to curcumin

are also referred to as curcuminoids. Compounds of that type are

considered intermediates in the biosynthesis of cyclic phenolic natural

products, the phenylphenalenones, which represent characteristic

constituents of the Haemodoraceae and Musaceae plant families.

Involvement of diarylheptanoids in phenylphenalenone biosynthesis has

been conﬁrmed by feeding experiments using a labelled precursor of that

type.^[5]More detailed studies to establish the occurrence of and exact

biosynthetic pathway to phenylphenalenones require synthesis of

diarylheptanoids as analytical standards and putative intermediates.

As putative intermediates of phenylphenalenone biosynthesis, diaryl-

hepta-4,6-dien-3-ones are of special interest. In the original synthesis of

diarylheptadienones, the Wittig reaction was used as the central step.^[6,7]

Since then many approaches to related diaryl dienones and other diaryl-

heptanoids have been elaborated^[8,9]mainly based on the aldol condensa-

tion^[10–12]and the Wittig-Horner reaction.^[13,14]We herein describe the

synthesis of new (E,E)-diarylhepta-4,6-dien-3-ones, which were prepared

via three diﬀerent approaches: Wittig reaction following the procedure of

Sakakibara et al.,^[6]aldol condensation, and Wittig-Horner reaction.

2. RESULTS AND DISCUSSION

2.1. Wittig Approach

The procedure described for the synthesis of 4,6-heptadien-3-ones^[6,7]

was found rather laborious and, in the case of phenolic compounds, gave

low yields. It starts from a phenylpropionic acid e.g., hydrocaﬀeic acid

(1), which after protection was treated subsequently with thionyl chlor-

ide, diazomethane, HBr, and triphenylphosphine. In the ﬁnal step,

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Scheme 1. Reagents and conditions: i: Ac₂O, Py, r.t., 8 h, 87 % for 2 and 75 %

for 9; ii: (COCl)₂, benzene, reﬂux, 45 min; iii: 1) CH₂N₂, benzene, 8^ꢀC, 30 min, 2)

r.t., 2 h; iv: HBr (48%), benzene, 5^ꢀC, 30 min, 48% based on 2; v: P (CH₅)₃,

6

benzene, r.t., 48 h, 80%; vi: 1) K₂CO₃, H₂O, 80^ꢀC, 10 min, 2) 7 or 9, benzene,

reﬂux, 48 h, 48% for 10 and 46% for 11 based on 6; vii: MeONa, MeOH, r.t.,

10 min, 82% for 12 and 76% for 13.

the phosphonium salt 6 was reacted with aldehyde 7 and 9, respectively

(Sch. 1).^[15]Two low-yield steps, the bromination (48%) and the Wittig

reaction (48% for 10 and 45% for 11) diminished total yield of com-

pounds 12 and 13 to only 13% and 11% respectively.

2.2. Aldol Condensation

As a result of the low total yields of the diarylheptanoids obtained by

the Wittig approach, further strategies were pursued. The synthesis of

dienone 14 was started from the commercially available ketone 15. The

phenolic hydroxyl group was protected as the benzoate ester because this

protection group does not interfere with preparation of a ketone enolate

with LDA and is furthermore advantegeous by the ease of removal by

treatment with mild base.^[16]The protected ketone 16 was treated with

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Scheme 2. Reagents and conditions: i: BzCl, Py, DMAP, DCM, r.t., 12 h, 90%;

ii: 1) LDA, THF, ꢁ78^ꢀC, 2) cinnamic aldehyde, 3) TMSCl, THF, r.t., 1 h, 40%;

iii: K₂CO₃, MeOH, r.t., 2 h, 49% from 17, 65% from 19; iv: 1) LDA, THF,

ꢁ78^ꢀC, 2) cinnamic aldehyde, 63%; v: TsOH(cat), C₆H₆, reﬂux, 10 min, 99%.

LDA at low temperature and the resulting enolate was reacted with

cinnamic aldehyde (Sch. 2). Reports had shown that the addition of

TMSCl to the reaction mixture drastically improved yields of die-

nones.^[17,18]However, in our case, analysis of the reaction mixture

showed a very slow formation of dienone from the TMS-ether 17.

Finally, the reaction was quenched and 17 was isolated in 40% yield

after chromatography. Treatment of TMS-ether 17 with K₂CO₃in

methanol eﬀected hydrolysis of protection group and subsequent dehy-

dration to give 14. Unfortunately, the reaction was accompanied by for-

mation of the retroaldol product, which reduced the yield of the desired

diarylheptanoid 14 to 49%. The aldol reaction was repeated without

adding TMSCl, and the intermediate product 18 was dehydrated with

TsOH, which resulted in a greater yield. The overall yield of 14 from

three steps (addition, dehydration and hydrolysis) was substantially

better (40%) than in the ﬁrst procedure (19% for two steps).

The starting material for the synthesis of dienone 12 was prepared in

a two-step procedure from 3,4-dihydroxybenzaldehyde 20 (Sch. 3).

Knoevenagel condensation with piperidinium acetate as a catalyst^[18,19]

gave ketone 21 and avoided the need for protection of the hydroxy

groups. There are no reports on chemoselective hydrogenation of

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Scheme 3. Reagents and conditions: i: Me₂CO, MeCN, AcOH, C₅H₁₀NH, reﬂux,

4 h, 48%; ii: HCO₂NH₄, Pd/C, Me₂CO, MeOH, r.t., 1 h, 90%; iii: EtOCH¼CH₂,

Et₂O, r.t., 24 h, 95%; iv: 1) LDA, THF, ꢁ78^ꢀC, 2) cinnamic aldehyde, 3)

TsOH(cat), MeOH, r.t., 5 min, 4) TsOH, THF, C₆H₆, r.t., 48 h, 38%; v: 1)

LDA, THF, ꢁ78^ꢀC, 2) cinnamic aldehyde, TMSCl, 3) DBU, THF, reﬂux, 3 h,

44 %; vi: TsOH(cat), MeOH, r.t., 5 min, 96%.

double bond in the unprotected ketone 21. Transfer hydrogenation of 21

with ammonium formate was performed in order to simplify the proce-

dure and to avoid the use of hydrogen gas. The problem of excessive

reduction resulting in the saturated alcohol, which heavily diminished the

yield of the desired ketone,^[20,21]was avoided by adding acetone to reac-

tion mixture.^[22,23]The ketone 22 was obtained in 90% yield.

Subsequent steps required the selection of a protecting group for the

catechol moiety. It is known^[5]that the ﬁnal compound 12 is rather

unstable and would not withstand the harsh conditions used for depro-

tection of typical protection groups in catechols.^[16]On the other hand,

the protection group had to be stable during the aldol reaction and

puriﬁcation. The ethoxyethyl group (EE) was chosen, because this pro-

tection group fulﬁlls the above requirements, gives good yields, and does

not hinder the reaction site. The drawback is the introduction of two

chiral centers into the molecule, which generates two diastereomers

that complicate the interpretation of NMR spectra to some extent.

Thus, ketone 22 was protected as EE ether 23, and the latter was used

in the aldol reaction. However, we obtained very modest yields (38–44%)

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of compound 12 in the elimination step under both basic (DBU) and

acidic (TsOH) conditions. Again, the major concurrent reaction was

the retroaldol process.

Oxa-analogues of diarylheptanoids (e.g., 2-hydroxy-5-phenylpenta-

noic acid benzyl ester) are accessible by enantioselective aldol addition

using benzyl acetate derived silyl ketene acetal.^[24]In our case enantios-

electivity was not necessary because dehydration resulted in the subse-

quent loss of stereochemistry. Accordingly, the oxa-analogue of

diarylheptanoid 12 was synthesized by means of an aldol-type condensa-

tion of cinnamic aldehyde with protected acetic acid 3,4-dihydroxybenzyl

ester. The procedure started with 3,4-dioxybenzaldehyde 20, which was

protected as the EE-ether 25^[25]and reduced with NaBH₄. The obtained

alcohol 26 was acetylated to give acetate 27. These steps gave almost

quantitative yields and did not require additional puriﬁcation. The reac-

tion of cinnamic aldehyde 7 with the anion of ester 27 led to hydroxy

ester 28 in a good yield (81%). The dehydration step was carried out in

the presence of acetic anhydride and DBU and the dienonate 29 was

1

isolated in 74% yield. The H NMR spectrum revealed a minor admix-

ture of cis-isomer of compound 29. The deprotected dienoate 30 (Sch. 4)

was extremely labile under acidic and basic conditions due to its benzylic

nature and in order to obtain compound 30 in high yields, compound 29

was treated with TsOH and the reaction quenched with pyridine to

ensure neutral conditions during the work up.

Scheme 4. Reagents and conditions: i: EtOCH¼CH₂, Et₂O, r.t., 3d, 91%; ii:

NaBH₄, CH₂Cl₂–MeOH, ꢁ5^ꢀC, 0.5 h, 99%; iii: Ac₂O, Py, CH₂Cl₂, r.t., 1 h,

99%; iv: 1) LDA, THF, ꢁ78^ꢀC, 2) cinnamic aldehyde, 0.5 h, 81%; v: Ac₂O,

DBU, C₆H₆, 90^ꢀC, 2.5 h, 74%; vi: TsOH(cat), MeOH, r.t., 5 min, 99%.

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2.3. Wittig-Horner Approach

Having such low yields, we reconsidered our approach and decided

to use the Wittig-Horner reaction. The starting material for the synthesis,

ester 32, was prepared from hydrocaﬀeic acid (1) in 92% yield. As

expected, the transformation of ester 32 into phosphonate 33 after pur-

iﬁcation gave the product in 87% yield (11% of starting material was

recovered). Phosphonate 33 was used under conditions of the Wittig-

Horner reaction proposed in the synthesis of shogaol^[26](Sch. 5).

However, the use of NaH as a base resulted in moderate yields of the

product, which were compatible with yields of the aldol reaction.

Conditions^{[13,27,28,29]}employing LiCl and an organic base were also unsa-

tisfactory, as the dienone was contaminated with low-molecular weight

byproducts. When the latter reaction was performed with only DBU as a

base, the desired compound 24 was isolated in 71% yield. Deprotection

was accomplished without complication to give dienone 12 in 96%. The

overall yield in the latter procedure over ﬁve steps, using DBU in the

condensation, was 54%.

It was desirable to synthesise a ﬂuorine containing analogue of 12 and

13 for use in biosynthesis studies. In order to minimise the stereoelectronic

Scheme 5. Reagents and conditions: i: AcCl, MeOH, r.t., 12 h, 99%; ii:

EtOCH¼CH₂, Et₂O, r.t., 24 h, 92%; iii: 1) MeP(O)(OMe)₂, THF, ꢁ78^ꢀC, 2)

MeLi 3) 32, 1 h, 87%; iv: 1) NaH, THF, 0^ꢀC, 2) 7, reﬂux, 3 h, 43%; v: DBU, 7

or 34, THF, reﬂux, 4 h, 71% for 24 and 44% for 36; vi: TsOH(cat), MeOH, r.t.,

5 min, 96% for 12.

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pertubation caused by the introduction of ﬂuorine, the 4⁰⁰-hydroxyl group

of 13 was substituted for ﬂuorine. As the Wittig-Horner approach to

synthesize gave better yields compared with the Wittig synthesis and

aldol reaction, this method was chosen for the synthesis of the ﬂuoro-

analogue of 13. The starting material, 3-(4-ﬂuorophenyl)-2-propenal

(34), was prepared from p-ﬂuorobenzaldehyde and acetaldehyde by

aldol condensation.^[30]The product was puriﬁed via preparative TLC.

Condensation of the aldehyde 34 with phosphonate 33 and deprotection

in a one-pot process without isolation of the ethoxyethyl derivative 35

gave the ﬂuorodiarylheptanoid (36) as the free catechol.

3. CONCLUSIONS

The synthesis of diarylheptanoids and analogues has been achieved

by three diﬀerent strategies. The improved Wittig-Horner approach

proved the most suitable scheme for synthesis of (E,E)-diaryl-4,6-hepta-

dien-3-ones. A total yield of 54% in ﬁve steps was obtained compared

with 40% (from 22) in the aldol and approximately 12% in the Wittig

approach. Owing to the high overall yield, the proposed Wittig-Horner

approach is also suitable for syntheses of diarylhepta-4,6-dien-3-ones and

further diarylheptanoids in labelled form. Compound 12 and new diaryl-

heptanoids 13 and 14 have been suggested as biosynthetic intermediates

of phenylphenalenone biosynthesis, which after o-hydroxylation of the

phenolic ring (compound 14) and oxidation to o-quinones may represent

substrates for intramolecular Diels-Alder reaction.

4. EXPERIMENTAL SECTION

4.1. General Methods

Melting points were measured in a Buchi B-540 apparatus and are

uncorrected. Infrared spectra were recorded on a FTIR, Bruker

EQUINOX 55 spectrometer and only characteristic absorptions are

reported. NMR spectra were recorded on a Bruker DRX 500 spectro-

meter at 500.13 MHz (¹H) and 125.75 MHz (¹³C), respectively, using

standard Bruker software. TMS was used as internal standard.

¹H NMR, ¹H–¹H COSY, HMBC, and HMQC experiments were

recorded in a 2.5 mm inverse detection microprobe head. Broadband

decoupled ¹³C and DEPT spectra were run using a 2.5 mm broadband

microprobe head. Chemical shifts are reported in ꢀ values and coupling

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constants are in Hz. MS and HRMS data were obtained with a

Micromass MasSpec mass spectrometer (70 eV). The ratio m/z and rela-

tive intensities (%) are indicated for the signiﬁcant peaks. Column chro-

matography was performed on Merck silica gel 60 (0.04–0.2 mm).

Solvents were dried and freshly distilled according to common practice.

All reactions were carried out under positive nitrogen pressure. Reactions

were monitored by TLC on precoated silica gel 60 F-254 plates (Merck),

and visualization of the compounds was accomplished by UV light

and/or spraying with FeCl₃solution.

4.2. Wittig Synthesis

4.2.1. (E)-Acetoxycinnamaldehyde (9)

Compound 9 was synthesized from p-cumaraldehyde (8) by standard

acetylation procedure using acetic anhydride in pyridine. ¹H NMR (acet-

one-d₆): ꢀ 2.28 (3H, s, AcO), 6.75 (1H, dd, J ¼ 16.4, 7.6 Hz, H-2), 7.24

(2H, d, J ¼ 8.8 Hz, H-3⁰and H-5⁰), 7.68 (1H, d, J ¼ 16.4 Hz, H-3), 7.76

(2H, d, J ¼ 8.8 Hz, H-2⁰and H-6⁰), 9.71 (1H, d, J ¼ 7.6 Hz, H-1); EIMS:

m/z 190 (M^þ, 26), 148 (100), 131 (29), 120 (50).

4.2.2. (4E,6E)-1-(3,4-Diacetoxyphenyl)-7-(4-Acetoxyphenyl)-

Hepta-4,6-dien-3-one (11)

The Wittig reaction of the phosphonium bromide 6 with aldehyde 7

and 9, respectively, was performed using the procedure of Bazan et al.^[7]

Phosphoniumbromide 6 (0.112 g, 0.185 mmol) was dissolved in hot

water (1.5 mL), and 0.5 mL of an aqueous solution of K₂CO₃(0.027 g,

0.2 mmol) were added dropwise with stirring. The precipitated phosho-

nium ylide was separated, dissolved in benzene, dried by azeotropic

evaporation, and redissolved in dry benzene. Acetoxy-trans-cinnamalde-

hyde (9) (0.034 g, 0.19 mmol) was added, and the mixture was reﬂuxed

for 48 h. The red solution was evaporated, and after chromatography

on a silica gel column with hexane-acetone 6:1 as eluent, gave 0.037 g

(46%) compound 11, M.p. 127–129^ꢀC. IR (KBr): (ꢁ_maxcm^ꢁ1) 2982, 1782,

1

1764, 1681, 1593, 1505, 1371, 1218, 1006, 886, 839; H NMR (CDCl₃): ꢀ

2.27 (3H, s, AcO), 2.28 (3H, s, AcO), 2.30 (3H, s, AcO), 2.92 (2H,

t, J ¼ 7.0 Hz, H-2), 2.97 (2H, t, J ¼ 7.0 Hz, H-1), 6.26 (1H,

d, J ¼ 15.4 Hz, H-4), 6.81 (1H, d, J ¼ 15.4, 10.8 Hz, H-6), 6.92

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(1H, d, J ¼ 15.4 Hz, H-7), 7.05 (1H, d, J ¼ 1.5 Hz, H-2⁰), 7.09 (m, H-5⁰, H-

6⁰, H-3⁰⁰and H-5⁰⁰), 7.30 (1H, dd, J ¼ 15.4, 10.8 Hz, H-5), 7.47 (2H, d,

J ¼ 8.5 Hz, H-2⁰⁰and H-6⁰⁰); ¹³C NMR (CDCl₃): ꢀ 20.6 (CH₃CO), 20.6

(CH₃CO), 21.1 (CH₃CO), 29.4 (C-1), 41.9 (C-2), 122.0 (C-3⁰⁰and C-5⁰⁰),

123.3 (C-2⁰and C-5⁰), 126.6 and 126.8 (C-6 and C-6⁰), 128.3 (C-2⁰⁰and C-

6⁰⁰), 129.5 (C-4), 140.2 (C-1⁰), 134.9 (C-1⁰⁰), 140.3 (C-4⁰), 140.4 (C-7),

141.9 (C-3⁰), 142.7 (C-5), 151.3 (C-4⁰⁰), 168.3 (CH₃CO), 168.4 (CH₃CO),

169.2 (CH₃CO),198.8 (C-3); EIMS: m/z 436 (M^þ, 31), 393 (69), 352

(54), 310 (39), 187 (60), 173 (100). HRMS: Calcd. for C₂₅H₂₄O₇:

436.1522, Found: 436.1518.

4.2.3. (4E,6E)-1-(3,4-Dihydroxyphenyl)-7-Phenylhepta-4,6-

dien-3-one (12)

Compound 12 was prepared from dihydrocaﬀeic acid (1) as described

by Bazan et al.^[7]For analytical data, see 4.3.12. The intermediate

phosphonium bromide 6 was also used for the preparation of (4E,6E)-

1-(3,4-hydroxyphenyl)-7-(4-hydroxyphenyl)-hepta-4,6-dien-3-one (13).

4.2.4. (4E,6E)-1-(3,4-Dihydroxyphenyl)-7-(4-Hydroxyphenyl)-

Hepta-4,6-dien-3-one (13)

For deprotection, 120 mL of 1 M solution of NaOMe in abs.

MeOH were added dropwise within 5 min to a stirred solution

of compound 11 (0.037 g, 0.085 mmol) in abs. MeOH (1 mL). The mixture

turned deep red and was stirred for another 5 min. Water (1 mL)

was added and after 5 min the alkaline mixture was acidiﬁed to pH 5.5

by the dropwise addition of 0.5 M HCl. The solution was extracted

with CHCl₃and puriﬁed by preparative TLC (CHCl₃:MeOH 19:1).

¹H NMR (acetone-d₆): ꢀ 2.76 (2H, t, J ¼ 7.9 Hz, H-1), 2.86 (2H,

t, J ¼ 7.9 Hz, H-2), 6.25 (1H, d, J ¼ 15.5 Hz, H-4), 6.57 (1H, dd, J ¼ 8.0,

2.1 Hz, H-6⁰), 6.72 (1H, d, J ¼ 8.0 Hz, H-5⁰), 6.73 (1H, d, J ¼ 2.1 Hz, H-2⁰),

6.86 (2H, d, J ¼ 8.8 Hz, H-3⁰⁰and H-5⁰⁰), 6.89 (1H, dd, J ¼ 15.5, 10.5 Hz,

H-6), 7.01 (1H, d, J ¼ 15.5 Hz, H-7), 7.38 (1H, dd, J ¼ 15.5, 10.5 Hz, H-5),

7.44 (2H, d, J ¼ 8.8 Hz, H-2⁰⁰and H-6⁰⁰); ¹³C NMR (acetone-d₆): ꢀ 30.3

(C-1), 42.8 (C-2), 115.9 (C-5⁰), 116.3 (C-2⁰), 116.6 (C-3⁰⁰and C-5⁰⁰), 120.4

(C-6⁰), 125.0 (C-6), 129.0 (C-1⁰⁰), 129.3 (C-4), 129.8 (C-2⁰⁰and C-6⁰⁰), 134.2

(C-1⁰), 142.2 (C-7), 143.7 (C-4⁰), 144.1 (C-5), 145.8 (C-3⁰), 159.5 (C-4⁰⁰),

199.4 (C-3); EIMS: m/z 310 (M^þ, 92), 173 (100). HRMS: Calcd.

for C₂₅H₂₄O₇: 310.1207, Found: 310.1205.

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4.3. Aldol Condensation

4.3.1. 4-(4-Benzoyloxyphenyl)-Butan-2-one (16)

A solution of ketone 15 (0.98 g, 6 mmol), benzoyl chloride (0.77 mL,

6.6 mmol), pyridine (1.06 mL, 13.2 mmol) and DMAP(0.09 g, 0.7 mmol)

in CH₂Cl₂(30 mL) was stirred at room temperature. After 4 h the solu-

tion was diluted with CH₂Cl₂, washed with water, brine, dried over

Na₂SO₄and evaporated to yield the product (2.0 g). The crude product

was crystallized from EtOAc-hexane to give the protected ketone 16

(1.46 g, 90%), M.p. 72.3–72.7^ꢀC. IR (KBr): (ꢁ_maxcm^ꢁ1) 2945, 2918,

1

1729, 1702, 1600, 1272, 1057, 883; H NMR (CDCl₃): ꢀ 2.14 (3H, s, H-

1), 2.76 (2H, t, J ¼ 7.6 Hz, H-3), 2.90 (2H, t, J ¼ 7.6 Hz, H-4), 7.11 (2H, d,

J ¼ 8.2 Hz, H-3⁰and H-5⁰), 7.22 (2H, d, J ¼ 8.2 Hz, H-2⁰and H-6⁰), 7.49

(2H, m, H-3⁰⁰and H-5⁰⁰), 7.61 (1H, t, J ¼ 7.5 Hz, H-4⁰⁰), 8.18 (2H, d,

J ¼ 7.9 Hz, H-2⁰⁰and H-6⁰⁰); ¹³C NMR (CDCl₃): ꢀ 29.1 (C-4), 30.1 (C-

1), 45.1 (C-3), 121.7 (C-3⁰and C-5⁰), 128.5 (C-3⁰⁰and C-5⁰⁰), 129.3 (C-2⁰

and C-6⁰), 129.5 (C-1⁰), 130.1 (C-2⁰⁰and C-6⁰⁰), 133.5 (C-4⁰⁰), 138.6 (C-1⁰⁰),

149.2 (C-4⁰), 165.3 (COO), 207.7 (C-2); EIMS: m/z 268 (M^þ, 19), HRMS:

Calcd. for C₁₇H₁₆O₃: 268.1099, Found: 268.1099.

4.3.2. (6E)-1-(4-Benzoyloxyphenyl)-7-Phenyl-5-

trimethylsilyloxy-hept-6-en-3-one (17)

To a stirred solution of LDA (1.6 mmol) in THF (5 mL) at ꢁ78^ꢀC

was added a solution of ketone 16 (0.295 g, 1.1 mmol) in THF (5 mL) via

syringe. After 15 min, cinnamic aldehyde (0.138 mL, 1.05 mmol) in THF

(5 mL) was added. The mixture was stirred for 30 min at the indicated

temperature and TMSCl (0.265 mL, 2 mmol) was added in one portion.

The cooling bath was removed and the solution was allowed to warm

to ambient temperature. After 4 h, saturated NaHCO₃was added and the

mixture was extracted with EtOAc. The organic phase was washed with

brine, dried, and evaporated. The obtained residue was separated

on a silica gel column with CH₂Cl₂:hexane as eluent to yield TMS-

ether 17 as a pale yellow oil (0.188 g, 40%). IR (neat): (ꢁ_maxcm^ꢁ1

)

3027, 2953, 1736, 1714, 1600, 1264, 1058, 841; ¹H NMR (CDCl₃): ꢀ

0.12 (9H, s, CH₃Si), 2.54 (1H, dd, J ¼ 4.8, 15.1 Hz, H-4a), 2.80 (3H, m,

H-4b and H-2), 2.92 (2H, t, J ¼ 7.7 Hz, H-1), 4.81 (1H, m, H-5), 6.17 (1H,

dd, J ¼ 6.4, 15.7 Hz, H-6), 6.55 (1H, d, J ¼ 15.7 Hz, H-7), 7.11 (2H, d,

J ¼ 8.5 Hz, H-3⁰and H-5⁰), 7.23 (2H, d, J ¼ 8.5 Hz, H-2⁰and H-6⁰),

7.25 (1H, tt, J ¼ 7.7, 1.3 Hz, H-4⁰⁰), 7.31 (2H, dd, J ¼ 7.7, 7.7 Hz, H-3⁰⁰

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and H-5⁰⁰), 7.36 (2H, d, J ¼ 7.7 Hz, H-2⁰⁰and H-6⁰⁰), 7.51 (2H, dd, J ¼ 7.7,

8.1 Hz, H-3⁰⁰⁰and H-5⁰⁰⁰), 7.62 (1H, tt, J ¼ 7.4, 1.3 Hz, H-4⁰⁰⁰), 8.18 (2H,

d, J ¼ 8.1 Hz, H-2⁰⁰⁰and H-6⁰⁰⁰); ¹³C NMR (CDCl₃): ꢀ 0.2 (CH₃Si), 28.8

(C-1), 46.1 (C-2), 51.1 (C-4), 70.2 (C-5), 121.6 (C-3⁰and C-5⁰), 126.5 (C-

2⁰⁰and C-6⁰⁰), 127.6 (C-4⁰⁰), 128.5 (C-3⁰⁰⁰and C-5⁰⁰⁰), 128.6 (C-3⁰⁰and C-

5⁰⁰), 129.3 (C-2⁰and C-6⁰), 129.6 (C-1⁰), 129.7 (C-7), 130.1 (C-2⁰⁰⁰

and C-6⁰⁰⁰), 131.7 (C-6), 133.5 (C-4⁰⁰⁰), 136.6 (C-1⁰⁰), 138.7 (C-1⁰⁰⁰), 149.2

(C-4⁰), 165.3 (COO), 207.8 (C-3); EIMS: m/z 472 (M^þ, 30), 447

(10), 382 (10), 367 (15), 325 (15), 261 (20), 247 (20), 205 (80).

HRMS: Calcd. for C₂₉H₃₂O₄Si: 472.2070, Found: 472.2074.

4.3.3. (6E)-1-(4-Benzoyloxyphenyl)-5-Hydroxy-7-

phenylhept-6-en-3-one (18)

To a stirred solution of LDA (1.57 mmol) in THF (5 mL) at ꢁ78^ꢀC

was added a solution of ketone 16 (0.35 g, 1.32 mmol) in THF

(5 mL) via a syringe. After 15 min, cinnamic aldehyde (0.17 mL,

1.31 mmol) in THF (5 mL) was added. The mixture was

stirred for 20 min at the indicated temperature and the reaction

was quenched with saturated NH₄Cl. The solution was allowed

to warm to ambient temperature and then extracted with EtOAc. The

organic

phase

was

washed

with

brine,

dried,

and

evaporated. The obtained residue was puriﬁed on a silica gel

column with EtOAc:hexane as eluent to give 0.33 g (63%) of ketol

18, M.p. (hexane-ether) 74.2–75.0^ꢀC. IR (KBr): (ꢁ_maxcm^ꢁ1) 3446, 3035,

2933, 1736, 1690, 1288, 1061, 960; ¹H NMR (acetone-d₆): ꢀ 2.70 (2H, dd,

J ¼ 15.6, 4.8 Hz, H-4a), 2.76 (2H, dd, J ¼ 15.6, 8.1 Hz, H-4b), 2.91 (4H, s,

H-1 and H-2), 4.77 (1H, m, H-5), 6.34 (1H, dd, J ¼ 15.9, 5.7 Hz, H-6),

6.65 (1H, dd, J ¼ 15.9, 1.3 Hz, H-7), 7.17 (2H, d, J ¼ 8.6 Hz, H-3⁰and H-

5⁰), 7.23 (1H, tt, J ¼ 7.3, 1.3 Hz, H-4⁰⁰), 7.31 (2H, dd, J ¼ 7.3, 7.7 Hz, H-3⁰⁰

and H-5⁰⁰), 7.32 (2H, d, J ¼ 8.6 Hz, H-2⁰and H-6⁰), 7.41 (2H, d, J ¼ 7.7 Hz,

H-2⁰⁰and H-6⁰⁰), 7.59 (2H, dd, J ¼ 7.5, 8.1 Hz, H-3⁰⁰⁰and H-5⁰⁰⁰), 7.72 (1H,

tt, J ¼ 7.5, 1.3 Hz, H-4⁰⁰⁰), 8.17 (2H, d, J ¼ 8.1 Hz, H-2⁰⁰⁰and H-

6⁰⁰⁰); ¹³C NMR (acetone-d₆): ꢀ 29.5 (C-1), 45.5 (C-2), 50.9 (C-4), 69.2 (C-

5), 122.5 (C-3⁰and C-5⁰), 127.2 (C-2⁰⁰and C-6⁰⁰), 128.2 (C-4⁰⁰), 129.4 (C-3⁰⁰

and C-5⁰⁰), 129.6 (C-3⁰⁰⁰and C-5⁰⁰⁰), 129.8 (C-7), 130.2 (C-2⁰and C-6⁰),

130.6 (C-1⁰), 130.7 (C-2⁰⁰⁰and C-6⁰⁰⁰), 133.4 (C-6), 134.6

(C-4⁰⁰⁰), 138.0 (C-1⁰⁰), 140.2 (C-1⁰⁰⁰), 150.3 (C-4⁰), 165.6 (COO), 208.6

(C-3); EIMS: m/z 400 (M^þ, 14), 382 (28), 268 (52),

331 (56), 105 (100). HRMS: Calcd. for C₂₆H₂₄O₄: 400.1675,

Found: 400.1674.

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4.3.4. (4E,6E)-1-(4-Benzoyloxyphenyl)-7-Phenylhepta-4,6-

dien-3-one (19)

To a solution of ketol 18 (0.29 g, 0.73 mmol) in benzene (10 mL) was

added a catalytical amount of TsOH and activated molecular sieves 4 A.

The resulting solution was heated under reﬂux for 10 min, cooled and

diluted with ether. The solution was washed with water, brine, dried, and

evaporated to give compound 19, M.p. (toluene) 92.7–94.7^ꢀC. The diene

19 was used in the next step without puriﬁcation. IR (KBr): (ꢁ_maxcm^ꢁ1

)

3068, 3035, 2933, 1737, 1730, 1680, 1664, 1264, 1059; ¹H NMR (CDCl₃):

ꢀ 2.93 (2H, t, J ¼ 7.3 Hz, H-2), 2.99 (2H, t, J ¼ 7.3 Hz, H-1), 6.28 (1H, d,

J ¼ 15.3 Hz, H-4), 6.86 (1H, dd, J ¼ 10.5, 15.6 Hz, H-6), 6.93 (1H, d,

J ¼ 15.6 Hz, H-7), 7.12 (2H, d, J ¼ 8.3 Hz, H-3⁰and H-5⁰), 7.26 (2H, d,

J ¼ 8.3 Hz H-2⁰, and H-6⁰), 7.34 (4H, m, H-5, H-3⁰⁰, H-4⁰⁰, and H-5⁰⁰), 7.46

(2H, J ¼ 8.1 Hz, H-2⁰⁰and H-6⁰⁰), 7.49 (2H, dd, J ¼ 8.1, 7.5 Hz, H-3⁰⁰⁰and

H-5⁰⁰⁰), 7.61 (1H, t, J ¼ 7.5 Hz, H-4⁰⁰⁰), 8.19 (2H, d, J ¼ 8.1 Hz, H-2⁰⁰⁰and

H-6⁰⁰⁰); ¹³C NMR (CDCl₃): ꢀ 29.6 (C-1), 42.3 (C-2), 121.7 (C-3⁰and C-5⁰),

126.7 (C-6), 127.3 (C-2⁰⁰and C-6⁰⁰), 128.6 (C-2⁰and C-6⁰), 128.8 (C-3⁰⁰⁰

and C-5⁰⁰⁰), 129.2 (C-4⁰⁰), 129.3 (C-1⁰), 129.4 (C-3⁰⁰and C-5⁰⁰), 130.2 (C-2⁰⁰⁰

and C-6⁰⁰⁰), 133.5 (C-4⁰⁰⁰), 136.0 (C-1⁰⁰), 138.9 (C-1⁰⁰⁰), 141.5 (C-7), 142.8

(C-5), 149.3 (C-4⁰), 165.3 (COO), 199.1 (C-3); EIMS: m/z 382 (M^þ, 70),

291 (6), 287 (10), 105 (100); HRMS: Calcd. for C₂₆H₂₂O₃: 382.1569,

Found: 382.1568.

4.3.5. (4E,6E)-1-(4-Hydroxyphenyl)-7-Phenylhepta-4,6-dien-

3-one (14) From 17

To a solution of TMS-ether 17 (0.163 g, 0.35 mmol) in MeOH (5 mL)

was added anhydrous K₂CO₃(0.097 g, 0.7 mmol) and the solution was

stirred at room temperature for 3 h. The reaction was quenched with

0.1 N HCl by adjusting to pH 8. The methanol was evaporated, and

the residue extracted with EtOAc, washed with brine, dried, and evapo-

rated. The obtained oil was separated on a silica gel column with CH₂Cl₂

as eluent to yield ketone 14 (0.048 g, 49%). For analytical data, see 4.3.6.

4.3.6. (4E,6E)-1-(4-Hydroxyphenyl)-7-Phenylhepta-4,6-dien-

3-one (14) From 19

To a solution of diene 19 (0.24 g, 0.63 mmol) in MeOH (12 mL) was

added anhydrous K₂CO₃(0.02 g, 0.15 mmol). The solution was stirred at

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Baranovsky et al.

room temperature for 0.5 h and reaction was quenched with 0.1 N HCl by

adjusting to pH 8. Water was added, and the mixture was extracted with

EtOAc. The organic phase was washed with brine, dried, and evaporated.

The obtained oil was puriﬁed as above to yield ketone 14 (0.11 g, 65%),

M.p. (hexane-ether) 129.3–130.0^ꢀC. IR (neat): (ꢁ_maxcm^ꢁ1) 3359, 3027,

1

1664, 1645, 1614, 1223; H NMR (CDCl₃): ꢀ 2.82 (2H, t, J ¼ 7.6, H-2),

2.83 (2H, t, J ¼ 7.6, H-1), 6.19 (1H, d, J ¼ 15.4 Hz, H-4), 6.67 (2H, d,

J ¼ 8.3 Hz, H-3⁰and H-5⁰), 6.84 (1H, d, J ¼ 15.4 Hz, H-7), 7.00 (2H, d,

J ¼ 8.5 Hz, H-2⁰and H-6⁰), 6.77 (1H, dd, J ¼ 15.4, 10.5, H-6), 7.23 (1H,

dd, J ¼ 15.4, 10.5 Hz, H-5), 7.26 (1H, m, H-3⁰⁰, H-4⁰⁰and H-5⁰⁰), 7.37 (2H,

d, J ¼ 8.5 Hz, H-2⁰⁰and H-6⁰⁰); ¹³C NMR (CDCl₃): ꢀ 30.3 (C-1), 42.9 (C-

2), 115.2 (C-3⁰and C-5⁰), 126.5 (C-6), 127.0 (C-2⁰⁰and C-6⁰⁰), 128.5 (C-3⁰⁰

and C-5⁰⁰), 128.9 (C-4⁰⁰), 129.2 (C-2⁰and C-6⁰), 129.2 (C-4), 133.3 (C-1⁰),

135.6 (C-1⁰⁰), 141.3 (C-7), 142.8 (C-5), 154.0 (C-4⁰), 199.7 (C-3); EIMS:

m/z 278 (M^þ, 100), 184 (30), 171 (50), 157 (90), 128 (70); HRMS: Calcd.

for C₁₉H₁₈O₂: 278.1307, Found: 278.1307.

4.3.7. (3E)-4-(3,4-Dihydroxyphenyl)-But-3-en-2-one (21)

3,4-Dihydroxybenzaldehyde 20 (1.38 g, 10 mmol) and acetone (5 mL,

66 mmol) were dissolved in degassed acetonitrile (30 mL). Subsequently,

piperidine (0.247 mL, 2.5 mmol), acetic acid (0.143 mL, 2.5 mmol) and

molecular sieves 4A (0.3 g) were added to the solution, and the resulting

purple mixture was reﬂuxed for 4 h. The solution was cooled and solvent

was evaporated. The residue obtained was dissolved in a small amount of

acetone and absorbed on silica gel, and acetone was evaporated. The

resultant material was puriﬁed on

a

silica gel column with

CHCl₃:EtOAc 95:5 as eluent to yield the yellow ketone 21 (0.95 g, 53%)

which was identical to the described compound,^[31]M.p. 177.3–178.0^ꢀC

(lit. 175–177^ꢀC, water). H NMR (acetone-d₆): ꢀ 2.28 (3H, s, H-1), 6.54

1

(1H, d, J ¼ 16.3 Hz, H-3), 6.88 (1H, d, J ¼ 8.1 Hz, H-5⁰), 7.06 (1H, dd,

J ¼ 1.7, 8.1 Hz, H-6⁰), 7.17 (1H, d, J ¼ 1.7 Hz, H-2⁰), 7.48 (1H, d,

J ¼ 16.3 Hz, H-4); ¹³C NMR (acetone-d₆): ꢀ 27.3 (C-1), 115.2 (C-5⁰),

116.4 (C-2⁰), 122.7 (C-6⁰), 125.3 (C-3), 127.9 (C-1⁰), 144.2 (C-4), 146.4

(C-3⁰), 148.8 (C-4⁰), 197.8 (C-2); EIMS: m/z 178 (M^þ, 84), 163 (100).

4.3.8. 4-(3,4-Dihydroxyphenyl)-Butan-2-one (22)

To a solution of ketone 21 (1.16 g, 6.5 mmol) and ammonium for-

mate (0.82 g, 13 mmol) in methanol (20 mL) was carefully added 10%

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Diarylheptanoids

1033

palladium on charcoal (0.67 g) and the resulted mixture was stirred

for 10 min at room temperature. To this was added acetone

(2.5 mL, 33 mmol) and the solution was stirred for another 50 min

after which the catalyst was ﬁltered oﬀ and washed with CHCl₃,

and the combined ﬁltrates were evaporated. The obtained oil was pur-

iﬁed on a silica gel column with CHCl₃:EtOAc 80:20 as eluent to

yield the colorless ketone 22 (1.06 g, 90%), in all respects

identical to the described compound^[32]M.p. 85.5–85.8^ꢀC (lit.

85–86^ꢀC, ether). H NMR (acetone-d₆): ꢀ 2.08 (3H, s, H-1), 2.69 (4H,

1

m, H-3 and H-4), 6.52 (1H, dd, J ¼ 1.9, 8.1 Hz, H-6⁰), 6.69 (1H, d,

J ¼ 1.9 Hz, H-2⁰), 6.72 (1H, d, J ¼ 8.1 Hz, H-5⁰); ¹³C NMR (acetone-d₆):

ꢀ 29.8 (C-1), 29.7 (C-4), 46.6 (C-3), 116.0 and 116.2 (C-2⁰and C-5⁰),

120.2 (C-6⁰), 133.9 (C-1⁰), 143.9 (C-4⁰), 145.7 (C-3⁰), 207.8 (C-2); EIMS:

m/z 180 (M^þ, 80), 137 (50), 123 (100); HRMS: Calcd. for

C₁₀H₁₂O₃: 180.0786, Found: 180.0787.

4.3.9. 4-[3,4-bis-(1-Ethoxyethoxy)-Phenyl]-Butan-2-one (23)

Pyridinium p-toluenesulfonate (0.18 g, 10 mol%) was added to a

solution of ketone 22 (1.29 g, 7.15 mmol) in ethyl ether (25 mL) and

vinyl ethyl ether (15 mL). The resulting solution was stirred for 24 h

at room temperature. When the reaction was complete, the

solution was diluted with hexane, separated from the catalyst by decant-

ing, washed with water, brine, dried over Na₂SO₄, and evaporated to

give ketone 23 as oil (2.20 g). The product was suﬃciently pure

for using in the next step. A small amount was puriﬁed for an analytical

purposes on a silica gel column with CH₂Cl₂as eluent to give a slightly

yellow oil in 95% yield. IR (neat): (ꢁ_maxcm^ꢁ1) 2982, 2936, 1715,

1

1600, 1263, 1107, 947; H NMR (acetone-d₆): ꢀ 1.13 (6H, m, CH₃CH₂),

1.41 (6H, m, CH₃CH), 2.08 (3H, s, H-1), 2.75 (4H, m, H-3 and

H-4), 3.55 (2H, m, CH₃CH₂), 3.79 (2H, m, CH₃CH₂), 5.32 (1H, q,

J ¼ 5.3 Hz, CH₃CH), 5.37 (1H, dq, J ¼ 5.3, 2.1 Hz, CH₃CH), 6.79 (1H,

dd, J ¼ 2.1, 8.2 Hz, H-6⁰), 6.96 (1H, d, J ¼ 2.1 Hz, H-2⁰), 6.97 (1H, d,

J ¼ 8.2 Hz, H-5⁰); ¹³C NMR (acetone-d₆): ꢀ 15.55/15.56 (CH₃CH₂),

20.86/20.89/20.90/20.93 (CH₃-CH), 29.76 (C-4), 29.83 (C-1), 45.33

(C-3),

62.34/62.38/62.42/62.47

(CH₃CH₂), 101.56/101.64/101.68/

101.75 (CH₃-CH), 120.42/120.46 and 120.52/120.58 (C-2⁰and C-5⁰),

123.06/123.10 (C-6⁰), 136.93/136.98 (C-1⁰), 146.92/146.99 (C-4⁰),

148.78/148.85 (C-3⁰), 207.24 (C-2); EIMS: m/z 324 (M^þ, 10), 252 (65),

180 (90), 123 (70); HRMS: Calcd. for C₁₈H₂₈O₅: 324.1937, Found:

324.1935.

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4.3.10. (4E,6E)-1-[3,4-bis-(1-Ethoxyethoxy)-Phenyl]-7-

Phenylhepta-4,6-dien-3-one (24)

To a stirred solution of LDA (1.12 mmol) in THF (5 mL) at ꢁ78^ꢀC

was added a solution of ketone 23 (0.246 g, 0.76 mmol) in THF (5 mL).

After 15 min, cinnamic aldehyde (0.092 mL, 0.7 mmol) in THF (5 mL)

was added. The almost colorless mixture was stirred for 30 min at the

indicated temperature and TMSCl (0.12 mL, 0.95 mmol) was added in

one portion. The cooling bath was removed and solution was allowed

to warm to ambient temperature. After 30 min DBU (0.12 mL, 0.8 mmol)

was added and the mixture was reﬂuxed for 3 h. The mixture was cooled

and the reaction quenched with saturated NH₄Cl and diluted with

EtOAc. The organic phase was washed with water and brine, dried and

evaporated. The obtained oil was puriﬁed on a silica gel column with

EtOAc:hexane 1:9 as eluent to give ketone 24 as yellow oil (0.147 g, 44%).

IR (neat): (ꢁ_maxcm^ꢁ1) 2977, 2932, 1683, 1660, 1619, 1265, 942; ¹H NMR

(CDCl₃): ꢀ 1.20 (6H, m, CH₃CH₂), 1.48 (6H, m, CH₃CH), 2.89 (4H, m,

H-1 and H-2), 3.57 (2H, m, CH₃CH₂), 3.84 (2H, m, CH₃CH₂), 5.30 (1H,

q, J ¼ 5.1 Hz, CH₃CH), 5.34 (1H, q, J ¼ 5.1 Hz, CH₃CH), 6.27 (1H, d,

J ¼ 15.5 Hz, H-4), 6.80 (1H, dd, J ¼ 1.3, 8.2 Hz, H-6⁰), 6.85 (1H, dd,

J ¼ 15.5, 10.5 Hz, H-6), 6.92 (1H, d, J ¼ 15.5 Hz, H-7), 6.94 (1H, d,

J ¼ 1.3 Hz, H-2⁰), 6.99 (1H, d, J ¼ 8.2 Hz, H-5⁰), 7.31 (2H, m, H-4⁰⁰and

H-5), 7.35 (2H, dd, J ¼ 7.8, 7.2 Hz, H-3⁰⁰and H-5⁰⁰), 7.45 (2H, d,

J ¼ 7.8 Hz, H-2⁰⁰and H-6⁰⁰); ¹³C NMR (CDCl₃): ꢀ 15.23, 15.27

(CH₃CH₂), 20.45/20.49/20.50/20.56 (CH₃-CH), 29.72 (C-1), 42.32 (C-2),

61.96/62.01/62.19/62.24 (CH₃CH₂), 101.06/101.13/101.13/101.20 (CH₃-

CH), 119.84/119.90 and 119.98/120.05 (C-2⁰and C-5⁰), 122.56/122.63

(C-6⁰), 126.66 (C-6), 127.24 (C-2⁰⁰and C-6⁰⁰), 128.45 (C-3⁰⁰and C-5⁰⁰),

129.21 (C-4⁰⁰), 129.56 (C-4), 135.99/136.03 (C-1⁰), 136.11 (C-1⁰⁰), 141.41

(C-7), 142.69 (C-5), 146.03/146.06 (C-4⁰), 147.78/147.82 (C-3⁰), 199.32 (C-

3); EIMS: m/z 438 (M^þ, 10), 366 (25), 321 (20), 294 (100), 157 (50);

HRMS: Calcd. for C₂₇H₃₄O₅: 438.2406, Found: 438.2405.

4.3.11. (4E,6E)-1-(3,4-Dihydroxyphenyl)-7-Phenylhepta-4,6-

dien-3-one (12) From 23

To a stirred solution of LDA (1.78 mmol) in THF (5 mL) at ꢁ78^ꢀC

was added a solution of ketone 23 (0.45 g, 1.36 mmol) in THF (5 mL) via

a syringe. The reaction mixture was stirred for 15 min and a solution of

cinnamic aldehyde (0.182 mL, 1.38 mmol) in THF (5 mL) was added. The

mixture was stirred for 30 min at the indicated temperature, after which

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the cooling bath was removed and the solution allowed to warm to

ambient temperature and stirred for an additional 1 h. The reaction mix-

ture was cooled again to ꢁ30^ꢀC, quenched with saturated NH₄Cl and

extracted with EtOAc. The organic phase was washed with brine, dried,

and evaporated. The obtained oil was dissolved in methanol (5 mL) and a

few crystals of TsOH were added. After 5 min the solvent was evaporated

without heating and the resulting dark orange oil was dissolved in a 1:1

mixture of benzene:THF (8 mL). TsOH (0.026 g, 0.14 mmol) was added

and the mixture was stirred for 48 h at room temperature. The solvent

was evaporated and the residue was separated on a silica gel column with

EtOAc:hexane 3:7 as eluent to give ketone 12 as yellow oil (0.15 g, 38%).

For analytical data, see 4.3.12.

4.3.12. (4E,6E)-1-(3,4-Dihydroxyphenyl)-7-Phenylhepta-4,6-

dien-3-one (12) From 24

To a solution of ketone 24 (0.308 g, 0.7 mmol) in methanol (5 mL),

TsOH (0.010 g, 0.05 mmol) was added. After 5 min the solvent was evap-

orated without heating and the resulting dark orange oil was puriﬁed on

a silica gel column with EtOAc:hexane 3:7 as eluent to give ketone 12

(0.197 g, 96%). IR (neat): (ꢁ_maxcm^ꢁ1) 3357, 3028, 1642, 1610, 1281, 997;

¹H NMR (CDCl₃): ꢀ 2.88 (2H, t, J ¼ 7.2 Hz, H-1), 2.90 (2H, t, J ¼ 7.2 Hz,

H-2), 6.28 (1H, d, J ¼ 15.3 Hz, H-4), 6.65 (1H, dd, J ¼ 2.0, 8.2 Hz, H-6⁰),

6.76 (1H, d, J ¼ 2.0 Hz, H-2⁰), 6.79 (1H, d, J ¼ 8.2 Hz, H-5⁰), 6.87 (1H, dd,

J ¼ 10.3, 15.3 Hz, H-6), 6.95 (1H, d, J ¼ 15.3 Hz, H-7), 7.35 (4H, m, H-5,

H-3⁰⁰, H-4⁰⁰and H-5⁰⁰), 7.47 (2H, d, J ¼ 7.2 Hz, H-2⁰⁰and H-6⁰⁰);

¹³C NMR (CDCl₃): ꢀ 29.7 (C-1), 42.5 (C-2), 115.2 and 115.4 d (C-2⁰

and C-5⁰), 120.4 (C-6⁰), 127.7 (C-6), 127.3 (C-2⁰⁰and C-6⁰⁰), 128.9 (C-3⁰⁰

and C-5⁰⁰), 129.2 (C-4⁰⁰), 129.5 (C-4), 133.9 (C-1⁰), 136.0 (C-1⁰⁰), 141.5 (C-

7), 142.2 (C-4⁰), 142.9 (C-5), 143.9 (C-3⁰), 199.9 (C-3); EIMS: m/z 294

(M^þ, 100), 223 (15), 184 (30), 171 (50), 157 (100), 128 (70); HRMS:

Calcd. for C₁₉H₁₈O₃: 294.1256, Found: 294.1255.

4.3.13. 3,4-Di-(1-Ethoxyethoxy)-Benzaldehyde (25)

Pyridinium p-toluenesulfonate (0.75 g, 10 mol%) was added to the

solution of aldehyde 20 (4.14 g, 30 mmol) in diethyl ether (30 mL) and

vinyl ethyl ether (37 mL). The resulting solution was stirred for 3 d at

room temperature. When protection was complete, the solution was

diluted with hexane, separated from the catalyst by decanting, washed

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Baranovsky et al.

with water, brine, dried over Na₂SO₄, and evaporated (8.46 g). The prod-

uct was further puriﬁed on a silica gel column with EtOAc:hexane 1:9 as

eluent to give aldehyde 25 (7.67 g, 91%). IR (neat): (ꢁ_maxcm^ꢁ1) 2978,

2934, 2897, 1695, 1596, 1582, 1512, 1435, 1382, 1344, 1271, 1230;

¹H NMR (acetone-d₆): ꢀ 1.17 (6H, m, CH₃CH₂), 1.50 (6H, m,

CH₃CH), 3.58 (2H, m, CH₃CH₂), 3.80 (2H, m, CH₃CH₂), 5.45 (1H,

dq, J ¼ 1.9, 5.4 Hz, CH₃CH), 5.59 (1H, q, J ¼ 5.4 Hz, CH₃CH), 7.27

(1H, d, J ¼ 8.5 Hz, H-5), 7.56 (1H, m, H-6), 7.60 (1H, d, J ¼ 2.0 Hz, H-

2), 9.82 (1H, s, CHO); ¹³C NMR (acetone-d₆): ꢀ 15.50/15.52 (CH₃CH₂),

20.54/20.55/20.66/20.70 (CH₃CH), 63.08/63.10/63.26/63.28 (CH₃CH₂),

101.84/101.87/102.44/102.45 (CH₃CH), 118.39/118.47 (C-5), 119.60/

119.81 (C-2), 127.73/127.77 (C-6), 132.43/132.46 (C-1), 148.85/148.90

(C-3), 154.99/155.00 (C-4), 192.73 (CHO). HRMS: Calcd. for

C₁₅H₂₂O₅: 282.1467, Found: 282.1473.

4.3.14. [3,4-bis-(1-Ethoxyethoxy)-Phenyl]-Methanol (26)

Sodium borohydride (0.20 g, 5.26 mmol) was added portionwise to a

solution of aldehyde 25 (5.03 g, 17 mmol) in a mixture of CH₂Cl₂–MeOH

(50 mL, 1:1) at ꢁ5^ꢀC over 5 min. The resulting solution was stirred for

0.5 h and then the reaction was quenched with solid NH₄Cl followed by

addition of water. The organic phase was separated, washed with brine,

dried, and evaporated to give alcohol 26 as pale yellow oil (5.10 g). The

product was used without puriﬁcation. IR (neat): (ꢁ_maxcm^ꢁ1) 3453, 2982,

2936, 2891, 1500, 1267, 1034; ¹H NMR (acetone-d₆): ꢀ 1.14 (6H, m,

CH₃CH₂), 1.43 (6H, m, CH₃CH), 3.56 (2H, m, CH₃CH₂), 3.80 (2H, m,

CH₃CH₂), 4.54 (2H, brs, CH₂OH), 5.36 (1H, q, J ¼ 5.2 Hz, CH₃CH), 5.39

(1H, q, J ¼ 5.2 Hz, CH₃CH), 6.93 (1H, m, H-6), 7.03 (1H, d, J ¼ 8.1 Hz,

H-5), 7.11 (1H, d, J ¼ 2.1 Hz, H-2); ¹³C NMR (acetone-d₆): ꢀ 15.58

(CH₃CH₂), 20.90/20.93/20.93/20.97 (CH₃CH), 62.47/62.49/62.49/62.54

(CH₃CH₂), 64.33 (CH₂OH), 101.67/101.75/101.78/101.85 (CH₃CH),

118.79/118.97 (C-2), 120.28/120.40 (C-5), 121.57/121.61 (C-6), 138.16/

138.21 (C-1), 147.71/147.78 (C-4), 148.86/148.93 (C-3). HRMS: Calcd.

for C₁₅H₂₄O₅: 284.1624, Found: 284.1622.

4.3.15. Acetic acid 3,4-bis-(1-Ethoxyethoxy)-Benzyl ester (27)

To a solution of alcohol 26 (5.10 g, 17 mmol) and pyridine (1.91 mL,

23.8 mmol) in CH₂Cl₂(30 mL) at room temperature was added acetic

anhydride (1.93 mL, 20.4 mmol). The resulted solution was stirred for

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1 h and then saturated NaHCO₃was added. The organic phase was

separated, washed with brine, dried, and evaporated to give acetate 27

as a pale yellow oil (5.90 g). The product was used without puriﬁcation.

IR (neat): (ꢁ_maxcm^ꢁ1) 2982, 2945, 2891, 1738, 1509, 1038; ¹H NMR

(acetone-d₆): ꢀ 1.14 (6H, m, CH₃CH₂), 1.44 (6H, m, CH₃CH), 2.03

(3H, s, OAc), 3.57 (2H, m, CH₃CH₂), 3.80 (2H, m, CH₃CH₂), 5.00

(2H, s, CH₂OAc), 5.39 (2H, m, CH₃CH), 6.98 (1H, m, H-6), 7.08 (1H,

d, J ¼ 8.4 Hz, H-5), 7.14 (1H, d, J ¼ 1.9 Hz, H-2); ¹³C NMR (acetone-d₆):

ꢀ 15.54 (CH₃CH₂), 20.80/20.83/20.83/20.86 (CH₃CH and CH₃CO),

62.37/62.40/62.43/62.46 (CH₃CH₂), 66.16 (CH₂OAc), 101.61/101.68/

101.69/101.76 (CH₃CH), 119.99/120.09 (C-2⁰), 120.59/120.70 (C-5⁰),

123.50/123.54 (C-6⁰), 131.83/131.88 (C-1⁰), 148.69/148.75/148.78/148.83

(C-3⁰and C-4⁰), 170.82 (CO); HRMS: Calcd. for C₁₇H₂₆O₆: 326.1732,

Found: 284.1729.

4.3.16. (4E)-3-Hydroxy-5-phenylpent-4-enoic acid 3,4-bis-(1-

Ethoxyethoxy)-Benzyl ester (28)

To a stirred solution of LDA (3.6 mmol) in THF (10 mL) at ꢁ78^ꢀC

was added a solution of acetate 27 (1.02 g, 3 mmol) in THF (7 mL) via

a syringe. After 15 min cinnamic aldehyde (0.4 mL, 3 mmol) in THF

(5 mL) was added. The mixture was stirred for 20 min at the indicated

temperature and the reaction was quenched with saturated NH₄Cl. The

solution was allowed to warm to ambient temperature and extracted with

EtOAc. The organic phase was washed with brine, dried, and evaporated.

The obtained residue was puriﬁed on a silica gel column with

EtOAc:hexane 1:2 as eluent to give 1.15 g (81%) of hydroxy ester 28.

IR (neat): (ꢁ_maxcm^ꢁ1) 3471, 2982, 2932, 2895, 1734, 1505, 1267;

¹H NMR (C₆D₆): ꢀ 1.08 (6H, m, CH₃CH₂), 1.42 (6H, m, CH₃CH), 2.43

(1H, dd, J ¼ 15.4, 4.2 Hz, H-2a), 2.56 (1H, ddd, J ¼ 15.4, 8.3, 2.0 Hz, H-

2b), 3.40 (2H, m, CH₃CH₂), 3.74 (2H, m, CH₃CH₂), 4.69 (1H, m, H-3),

4.99 (1H, d, J ¼ 12.2 Hz, CH₂OCO), 5.05 (1H, dd, J ¼ 12.2, 4.9 Hz,

CH₂OCO), 5.25 (1H, q, J ¼ 5.2 Hz, CH₃CH), 5.30 (1H, q, J ¼ 5.2 Hz,

CH₃CH), 6.12 (1H, dd, J ¼ 16.1, 5.7 Hz, H-4), 6.59 (1H, d, J ¼ 16.1 Hz,

H-5), 6.89 (1H, brd, J ¼ 8.3 Hz, H-6⁰⁰), 7.02 (1H, m, H-5⁰⁰), 7.05 (1H, t,

J ¼ 7.5 Hz, H-4⁰), 7.12 (2H, dd, J ¼ 8.5, 7.5 Hz, H-3⁰and H-5⁰), 7.21

(2H, d, J ¼ 8.5 Hz, H-2⁰and H-6⁰), 7.23 (1H, s, H-2⁰⁰); ¹³C NMR

(C₆D₆): ꢀ 15.40/15.43 (CH₃CH₂), 20.54/20.58/20.59/20.62 (CH₃CH),

42.13/42.15

(CH₃CH₂), 66.25/66.28 (CH₂OCO), 69.07 (C-3), 101.13/101.22/101.24/

(C-2),

61.78/61.80/61.92/61.92/61.94/61.95/61.96/61.96

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101.24/101.26/101.33/101.35/101.38 (CH₃CH), 119.72/119.75/119.78/

119.80 (C-5⁰⁰), 120.27/120.33/120.43/120.51 (C-2⁰⁰), 123.23/123.25/

123.30/123.32 (C-6⁰⁰), 126.91 (C-2⁰and C-6⁰), 127.82 (C-4⁰), 128.80 (C-3⁰

and C-5⁰), 130.52/130.54 (C-5), 130.90/130.92/130.93/130.95 (C-1⁰⁰),

131.04/131.07 (C-4), 137.18 (C-1⁰), 148.47/148.51/148.58/148.62 (C-3⁰⁰),

148.61/148.67/148.70/148.77 (C-4⁰⁰), 171.67/171.69 (C-1). HRMS: Calcd.

for C₂₆H₃₄O₇: 458.2305, Found: 458.2300.

4.3.17. (2E,4E)-5-Phenylpenta-2,4-dienoic acid 3,4-bis-(1-

Ethoxyethoxy)-Benzyl ester (29)

To a solution of the hydroxy ester 28 (1.02 g, 2.17 mmol) and DBU

(0.79 mL, 5.2 mmol) in benzene (20 mL) was added acetic anhydride

(0.24 mL, 2.6 mmol). The solution was heated under reﬂux for 2.5 h,

cooled and evaporated. The residue was ﬁltered through a short silica

gel column to give 0.73 g (74%) of compound 29. IR (neat): (ꢁ_maxcm^ꢁ1

)

2979, 2933, 2891, 1715, 1626, 1501, 1129; ¹H NMR (C₆D₆): ꢀ 1.09 (6H, m,

CH₃CH₂), 1.43 (6H, m, CH₃CH), 3.40 (2H, m, CH₃CH₂), 3.76 (2H, m,

CH₃CH₂), 5.19 (2H, s, CH₂OCO), 5.26 (1H, q, J ¼ 5.2 Hz, CH₃CH), 5.31

(1H, q, J ¼ 5.2 Hz, CH₃CH), 6.01 (1H, d, J ¼ 15.4 Hz, H-2), 6.41 (1H, d,

J ¼ 15.4 Hz, H-5), 6.53 (1H, dd, J ¼ 15.4, 11.0 Hz, H-4), 6.98 (1H, dd,

J ¼ 8.2, 1.8 Hz, H-6⁰⁰), 7.07 (6H, m, H-2⁰- H-6⁰and H-5⁰⁰), 7.31 (1H, m, H-

2⁰⁰), 7.56 (1H, dd, J ¼ 15.4, 11.0 Hz, H-3); ¹³C NMR (C₆D₆): ꢀ 15.40/15.44

(CH₃CH₂), 20.62/20.65/20.66/20.70 (CH₃CH), 61.96/61.98/61.99/62.00

(CH₃CH₂), 66.12 (CH₂OCO), 101.28/101.30/101.39/101.42 (CH₃CH),

119.80/119.87 (C-5⁰⁰), 120.46/120.53 (C-2⁰⁰), 121.50 (C-2), 123.39/123.41

(C-6⁰⁰), 126.43 (C-4), 127.52 (C-2⁰and C-6⁰), 128.88 (C-3⁰and C-5⁰),

129.07 (C-4⁰), 131.45/131.47 (C-1⁰⁰), 136.42 (C-1⁰), 140.64 (C-5), 145.22

(C-3), 148.57/148.61 and 148.67/148.70 (C-3⁰⁰and C-4⁰⁰), 166.54 (C-1);

HRMS: Calcd. for C₂₆H₃₂O₆: 440.2199, Found: 440.2205.

4.3.18. (2E,4E)-5-Phenylpenta-2,4-dienoic acid

3,4-dihydroxybenzyl ester (30)

To a solution of the dienoate 29 (0.083 g, 0.18 mmol) in methanol

(1 mL) was added TsOH (10 mg, 0.005 mmol). After 5 min pyridine

(0.1 mL) and water were added. The organic phase was extracted with

EtOAc, washed with brine, dried, and evaporated to give compound 30

(0.057 g, quant), M.p. 108.8–110.6^ꢀC (aq. MeOH). IR (KBr): (ꢁ_maxcm^ꢁ1

)

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Diarylheptanoids

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1

3497, 3381, 2956, 2928, 2854, 1681, 1620, 1519, 1288, 1001; H NMR

(acetone-d₆): ꢀ 5.06 (2H, s, CH₂), 6.09 (1H, d, J ¼ 15.3 Hz, H-2), 6.78

(1H, dd, J ¼ 8.0, 2.0 Hz, H-6⁰⁰), 6.83 (1H, d, J ¼ 8.0 Hz, H-5⁰⁰), 6.93

(1H, d, J ¼ 2.0 Hz, H-2⁰⁰), 7.10 (2H, m, H-4 and H-5), 7.34 (1H, tt,

J ¼ 7.3, 1.5 Hz, H-4⁰), 7.39 (2H, ddd, J ¼ 8.5, 7.3, 1.5 Hz, H-3⁰and

H-5⁰), 7.47 (1H, ddd, J ¼ 15.3, 9.1, 1.2 Hz, H-3), 7.58 (2H, dd, J ¼ 8.5,

1.5 Hz, H-2⁰and H-6⁰); ¹³C NMR (acetone-d₆): ꢀ 66.6 (CH₂), 116.0 (C-

5⁰⁰), 116.7 (C-2⁰⁰), 121.2 (C-6⁰⁰), 122.1 (C-2), 127.2 (C-4), 128.0 (C-2⁰and

C-6⁰), 129.0 (C-1⁰⁰), 129.6 (C-3⁰and C-5⁰), 129.8, (C-4⁰), 137.1 (C-1⁰), 141.3

(C-5), 145.6 (C-3), 145.9 (C-3⁰⁰), 146.1 (C-4⁰⁰), 167.0 (C-1). HRMS: Calcd.

for C₁₈H₁₆O₄: 296.1049, Found: 296.1049.

4.4. Wittig-Horner Synthesis

4.4.1. 3-(3,4-Dihydroxyphenyl)-Propionic acid methyl ester (31)

To a solution of hydrocaﬀeic acid (1) (1.80 g, 10 mmol) in methanol

(30 mL) was added acetyl chloride (0.079 g, 1 mmol) and the resulting

solution was stirred at room temperature. After 12 h no starting material

was detected and the solvent was evaporated and the obtained oil was

dried thoroughly under vacuum. ¹H NMR (CDCl₃): ꢀ 2.54 (2H, t,

J ¼ 7.7 Hz, H-2), 2.78 (2H, t, J ¼ 7.7 Hz, H-3), 3.62 (3H, s, OMe), 6.56

(1H, dd, J ¼ 2.2, 8.2 Hz, H-6⁰), 6.65 (1H, d, J ¼ 2.2 Hz, H-2⁰), 6.71 (1H, d,

J ¼ 8.2 Hz, H-5⁰); ¹³C NMR (CDCl₃): ꢀ 30.3 (C-3), 35.9 (C-2), 51.8

(OCH₃), 115.4 (C-2⁰), 115.4 (C-5⁰), 120.6 (C-6⁰), 133.4 (C-1⁰), 142.0 (C-

4⁰), 143.6 (C-3⁰), 173.9 (COOCH₃).

4.4.2. 3-[3,4-bis-(1-Ethoxyethoxy)-Phenyl]-Propionic acid

methyl ester (32)

The dried ester 31 was dissolved in a mixture of diethyl ether (15 mL)

and ethyl vinyl ether (14.4 mL). Pyridinium p-toluenesulfonate (0.251 g,

10 mol%) was added to the solution and the resulting mixture was stirred

for 24 h at room temperature. When protection had been completed, the

solution was diluted with hexane, separated from the catalyst by decant-

ing, washed with water and brine, dried over Na₂SO₄, and evaporated to

yield an oily product (3.5 g). The product was puriﬁed on silica gel

column with CH₂Cl₂as eluent, giving a slightly yellow oil in 92%

yield. IR (neat): (ꢁ_maxcm^ꢁ1) 2982, 2936, 1738, 1600, 1505, 1263, 947;

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Baranovsky et al.

¹H NMR (acetone-d₆): ꢀ 1.14 (6H, m, CH₃CH₂), 1.43 (6H, m, CH₃CH),

2.59 (2H, t, J ¼ 7.6 Hz, H-2), 2.84 (2H, t, J ¼ 7.6 Hz, H-3), 3.56 (2H, m,

CH₃CH₂), 3.61 (3H, s, OCH₃), 3.81 (2H, m, CH₃CH₂), 5.34 (1H, q,

J ¼ 5.3 Hz, CH₃CH), 5.39 (1H, dq, J ¼ 5.3, 2.1 Hz, CH₃CH), 6.81 (1H,

dd, J ¼ 2.1, 8.2 Hz, H-6⁰), 6.70 (1H, d, J ¼ 2.0 Hz, H-2⁰), 6.70 (1H, d,

J ¼ 8.2 Hz, H-5⁰); ¹³C NMR (acetone-d₆) ꢀ 15.55/15.56 (CH₃CH₂),

20.86/20.89/20.90/20.93 (CH₃-CH), 30.94 (C-3), 36.17 (C-2), 51.56

(OCH₃), 62.37/62.40/62.47/62.52 (CH₃CH₂), 101.61/101.69/101.69/

101.76 (CH₃-CH), 120.44/120.46 and 120.53/120.58 (C-2⁰and C-5⁰),

123.10/123.14 (C-6⁰), 136.28/136.33 (C-1⁰), 147.15/147.23 (C-4⁰),

148.82/148.88 (C-3⁰), 173.35 (C-1); EIMS: m/z 324 (M^þ, 10), 252 (65),

180 (90), 123 (70); EIMS: m/z 340 (M^þ, 10), 268 (30), 196 (95), 123 (45);

HRMS: Calcd. for C₁₈H₂₈O₆: 340.1886, Found: 340.1885.

4.4.3. 4-[3,4-bis-(1-Ethoxyethoxy)-Phenyl]-2-

Ketobutylphosphonic acid dimethyl ester (33)

To a stirred solution of dimethyl methylphosphonate (2.03 mL,

19 mmol) in THF (30 mL) at ꢁ78^ꢀC was added a 1.6 N solution of

MeLi in ether (11.6 mL, 18.6 mmol) via a syringe. The resulting solution

was stirred for 1 h at the indicated temperature and ester 32 (2.36 g,

6.5 mmol) in THF (15 mL) was added dropwise at ꢁ78^ꢀC. After this

addition the cooling bath was removed and the reaction was allowed to

warm slowly to room temperature. The reaction was stirred at room

temperature for 3 h, quenched with saturated NH₄Cl, and extracted

with EtOAc. The organic phase was washed with brine, dried, and evap-

orated to give an oily material (2.9 g). The product was separated via a

silica gel column with CHCl₃as eluent to give the starting material

(0.23 g, 11%) followed by phosphonate 33 as pale yellow oil (2.45 g,

87%). IR (neat): (ꢁ_maxcm^ꢁ1) 2981, 1718, 1600, 1507, 1260, 1034, 948;

¹H NMR (acetone-d₆): ꢀ 1.14 (6H, m, CH₃CH₂), 1.42 (6H, m, CH₃CH),

2.79 (2H, t, J ¼ 7.4 Hz, H-4), 2.96 (2H, t, J ¼ 7.4 Hz, H-3), 3.18 (2H, d,

²J_H-P¼ 22.5 Hz, H-1), 3.55 (2H, m, CH₃CH₂), 3.69 (3H, s, OCH₃), 3.71

(3H, s, OCH₃), 3.80 (2H, m, CH₃CH₂), 5.33 (1H, q, J ¼ 5.4 Hz, CH₃CH),

5.39 (1H, dq, J ¼ 1.4, 5.4 Hz, CH₃CH), 6.81 (1H, dd, J ¼ 1.9, 8.0 Hz, H-

6⁰), 6.98 (1H, d, J ¼ 1.9 Hz, H-2⁰), 6.99 (1H, d, J ¼ 8.0 Hz, H-5⁰);

¹³C NMR (acetone-d₆): ꢀ 15.57/15.59 (CH₃CH₂), 20.88/20.92/20.96/

1

20.99 (CH₃CH), 29.48 (C-4), 41.58 (d, J_C-P¼ 126.5 Hz, C-1), 45.89/

45.90 (C-3), 53.04 (OCH₃), 53.09 (OCH₃), 62.42/62.45/62.55/62.59

(CH₃CH₂), 101.66/101.73/101.76/101.83 (CH₃CH), 120.46/120.52

and 120.56/120.64 (C-2⁰and C-5⁰), 123.15/123.19 (C-6⁰), 136.62/136.73

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Diarylheptanoids

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(C-1⁰), 147.01/147.08 (C-4⁰), 148.88/148.94 (C-3⁰), 201.64 (d, J_C-P¼ 6.0

Hz, C-2); EIMS: m/z 432 (M^þ, 10), 360 (5), 315 (20), 288 (100), 178 (65);

HRMS: Calcd. for C₂₀H₃₃O₈P: 432.1913, Found: 432.1921.

2

4.4.4. (4E,6E)-1-[3,4-bis-(1-Ethoxyethoxy)-Phenyl]-7-

Phenylhepta-4,6-dien-3-one (24), Using NaH as Base

To a stirred suspension of NaH (0.019 g of 60% dispersion in mineral

oil, 0.48 mmol) in THF (5 mL) at 0^ꢀC was added a solution of phospho-

nate 33 (0.210 g, 0.49 mmol) in THF (5 mL) via a syringe. When the

evolution of gas had ceased, the red solution was cooled to ꢁ30^ꢀC and

a solution of cinnamic aldehyde (0.06 mL, 0.46 mmol) in THF (3 mL) was

added. The cooling bath was removed, and the solution was warmed and

then reﬂuxed for 2 h until the red color had faded to yellow. The reaction

mixture was cooled, quenched with saturated NH₄Cl, and extracted with

EtOAc. The organic phase was washed with water and brine, dried, and

evaporated. The obtained oil was puriﬁed on a silica gel column with

EtOAc:hexane 1:9 as eluent to give ketone 24 (0.093 g, 43%). For analyt-

ical data, see 4.3.10.

4.4.5. (4E,6E)-1-[3,4-bis-(1-Ethoxyethoxy)-Phenyl]-7-

Phenylhepta-4,6-dien-3-one (24), Using DBU as Base

To a stirred solution of phosphonate 33 (0.271 g, 0.62 mmol) in THF

(6 mL) were added DBU (0.096 g, 0.63 mmol) and cinnamic aldehyde

(0.082 g, 0.62 mmol). The resulting solution was reﬂuxed for 4 h and

cooled. The solution was poured in water and the resulting mixture

was extracted with EtOAc. The organic phase was washed with water

and brine, dried and evaporated. The obtained oil was puriﬁed using the

method described above (4.4.4.) to yield ketone 24 (0.193 g, 71%).

For analytical data, see 4.3.10.

4.4.6. (4E,6E)-1-(3,4-Dihydroxyphenyl)-7-Phenylhepta-4,6-

dien-3-one (12)

For procedure and analytical data, see 4.3.12.

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Baranovsky et al.

4.4.7. 3-(4-Fluorophenyl)-2-Propenal (34)

To a solution of acetaldehyde (1.01 g, 8.95 mM) in ethanol (10 mL) at

0^ꢀC was added 3 M NaOH (4.88 mL, 12.21 mM) and stirring maintained

for 20 min.^[30]p-Fluorobenzaldehyde (0.394 g, 8.14 mM) in ethanol

(5 mL) was added dropwise and the reaction allowed to warm to room

temperature and stirred for 90 min. The mixture was poured into water

and adjusted to pH 7.0 by the addition of 1 M HCl. The mixture was

extracted with EtOAc, the organic extract washed with brine, dried

over Na₂SO₄and the solvent evaporated. Puriﬁcation by preparative

TLC (n-hexane:EtOAc 6:1) gave 34 (0.745 g, 61%) as a yellow oil. IR

(KBr): (ꢁ_maxcm^ꢁ1) 3067, 3031, 2181, 1683, 1621, 1497, 1450, 1419,

1305, 1279, 978, 942, 761. ¹H NMR (MeOH-d₄): ꢀ 6.65 (1H, dd,

0

J ¼ 16.3, 7.5 Hz, H-2), 7.13 (2H, dd, J_{H-3 ,H-5 –H-2 ,H-6}¼ 8.5 Hz, J_{H-3 ,}

¼ 9.0 Hz, H-3⁰, H-5⁰), 7.45 (1H, d, J ¼ 16.3 Hz, H-3), 7.57 (2H,

0

H-5⁰–F-4

0

dd, J_{H-2 ,H-6 –H-3 ,H-5}¼ 8.5 Hz, J_{H-2 ,H-6 –F-4}¼ 5.2 Hz, H-2 ,H-6 ), 9.69

(1H, d, J ¼ 7.5 Hz, H-1); ¹³C NMR (MeOH-d₄):

ꢀ

116.4 (d,

²J_C-F¼ 22 Hz, C-3⁰,5⁰), 128.3 and 128.4 (C-2 and C-1⁰), 130.5 (d,

³J_C-F¼ 9 Hz, C-2⁰,6⁰), 151.3 (C-3), 164.5 (d, J_C-F¼ 253 Hz, C-4⁰), 193.4

1

(C-1); EIMS: m/z 150 (M^þ, 100).

4.4.7. (4E,6E)-1-(3,4-Dihydroxyphenyl)-7-(4-Fluorophenyl)-

4,6-Heptadien-3-one (36)

A solution of freshly prepared aldehyde 34 (0.082 g, 0.55 mM), phos-

phonate 33 (0.235 g, 0.57 mM) and DBU (0.093 g, 0.61 mM) in THF

(10 mL) was heated under reﬂux for 4 h. The reaction mixture was

poured into water and extracted with EtOAc. The organic extract

was washed with brine and dried over Na₂SO₄. The EE derivative 35

was not isolated and removal of the solvent immediately resulted in

36 as an yellow oil. Puriﬁcation by preparative TLC (n-hexane:EtOAc

6:1) gave 36 (0.075 g, 44%). IR (KBr): (ꢁ_maxcm^ꢁ1) 3434, 2952, 1701,

1

1618, 1541, 1363, 1283, 1158, 1305, 1113, 995. H NMR (MeOH-d₄):

2.77 (2H, t, J ¼ 7.4 Hz, H-1), 2.88 (2H, t, J ¼ 7.4 Hz, H-2), 6.31 (1H, d,

J ¼ 15.4 Hz, H-4), 6.52 (1H, dd, J ¼ 8.2, 2.1 Hz, H-6⁰), 6.66 (1H, d,

J ¼ 2.1 Hz, H-2⁰), 6.67 (1H, d, J ¼ 8.2 Hz, H-5⁰), 6.92 (1H, dd, J ¼ 15.6,

00

10.6 Hz, H-6), 7.00 (1H, d, J ¼ 15.6 Hz, H-7), 7.08 (2H, dd, J_{H-3 ,H-5 –}

00

H-2⁰⁰,H-6⁰⁰

¼ 8.6 Hz, J_{H-3 ,H-5 –F-4}¼ 9.0 Hz, H-3 ,H-5 ), 7.36 (1H, dd,

00

J ¼ 15.4, 10.6 Hz, H-5), 7.55 (2H, dd, J_{H-2 ,H-6 –H-3 ,H-5}¼ 8.6 Hz,

00

J_{H-2 ,H-6 –F-4}¼ 5.4 Hz, H-2 ,H-6 ); ¹³C NMR (MeOH-d₄): ꢀ 31.0 (C-1),

00

43.3 (C-2), 116.4 and 116.5 (C-2⁰and C-5⁰), 116.7 (d, J_C-F¼ 22 Hz,

2

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Diarylheptanoids

1043

C-3⁰⁰, C-5⁰⁰), 120.6 (C-6⁰), 127.8 and 127.9 (C-6 and C-1⁰⁰), 130.4 (d,

³J_C-F¼ 8 Hz, C-2⁰⁰, C-6⁰⁰), 130.5 (C-4), 134.1 (C-1⁰), 141.6 (C-7), 144.5

(C-4⁰), 144.9 (C-5), 146.2 (C-3⁰), 164.5 (d, J_C-F¼ 247 Hz, C-4⁰⁰), 202.8

1

(C-3); EIMS: m/z 312 (M^þ, 98), 175 (100); HRMS: Calcd. for

C₁₉H₁₇O₃F: 312.1162, Found: 312.1156.

ACKNOWLEDGMENTS

The authors thank Dr. Neil J. Oldham and Janine Rattke, Jena, for

mass spectra. This investigation was supported ﬁnancially by the

Deutsche Forschungsgemeinschaft (Bonn) and the Fonds der

Chemischen Industrie (Frankfurt/Main).

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Article Doi

Synthesis of new biosynthetically important diarylheptanoids and their oxa- and fluoro-analogues by three different strategies

DOI: 10.1081/SCC-120016367

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