First total synthesis of cytotoxic diarylheptanoids, galeon, and pterocarine

Article abstract of DOI:10.1080/00397910601131015

The first total synthesis of cytotoxic diphenyl ether-type diarylheptanoids, galeon and pterocarine, was described in which the Ullmann reaction was employed at the final step for the diaryl ether formation of key intermediate, 1-(3-bromo-4-benzyloxypheny

Full text of DOI:10.1080/00397910601131015

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First Total Synthesis of Cytotoxic
Diarylheptanoids, Galeon, and Pterocarine
Qian Wang a , Jong‐Keun Son a & Yurngdong Jahng a
a College of Pharmacy, Yeungnam University , Gyeongsan, Korea
Published online: 09 Mar 2007.
To cite this article: Qian Wang , Jong‐Keun Son & Yurngdong Jahng (2007) First Total Synthesis of Cytotoxic
Diarylheptanoids, Galeon, and Pterocarine, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 37:5, 675-681, DOI: 10.1080/00397910601131015
To link to this article: http://dx.doi.org/10.1080/00397910601131015
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Synthetic Communicationsw, 37: 675–681, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601131015
First Total Synthesis of Cytotoxic
Diarylheptanoids, Galeon, and Pterocarine
Qian Wang, Jong-Keun Son, and Yurngdong Jahng
College of Pharmacy, Yeungnam University, Gyeongsan, Korea
Abstract: The first total synthesis of cytotoxic diphenyl ether-type diarylheptanoids,
galeon and pterocarine, was described in which the Ullmann reaction was employed
at the final step for the diaryl ether formation of key intermediate, 1-(3-bromo-4-ben-
zyloxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)heptan-3-one, assembled by a series of
cross-aldol condensation from 3-methoxy-4-benzyloxybenzaldehyde.
Keywords: aldol, cytotoxicity, diatrylheptanoid, galeon, pterocarine, Ullmann reaction
INTRODUCTION
Diarylheptanoids are a class of natural products containing the 1,7-diphenyl-
heptane skeleton and can be classified into three major groups: acyclics, cyclic
biphenyls ([7.0]-metacyclophanes), and cyclic diphenyl ethers (14-oxa-
[7.1]metaparacyclophanes).[1] Although linear diarylheptanoids and cyclic
biphenylheptanoids have been studied extensively on account of their
unique structures[2–5] and wide variety of biological properties,[6–19] studies
on diphenyl ether-type cyclic diarylheptanoids such as acerogenins
(1a–d),[20–26] galeon (1e),[27,28] and pterocarine (1f)[29] are mostly limited
to their isolation from natural sources. Their intriguing structures have led
to the establishment of a couple of strategic methods for the total
synthesis of 1a–d and their related acerosides.[30–32] However, there are
no reported synthetic pathways for 1e or 1f. The methods reported
previously from readily available compounds, however, are somewhat
Address correspondence to Yurngdong Jahng, College of Pharmacy, Yeungnam
University, Gyeongsan 712-749, Korea. E-mail: ydjahng@yumail.ac.kr
675

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Q. Wang, J.-K. Son, and Y. Jahng
lengthy and are not suitable to apply to the synthesis of galeon and its related
diarylheptanoids.
Recent findings on the potent cytotoxic activity of 1e against selected
cancer cell lines[33] and the inhibitory activity to the cell cycle at the G0/G1
phase as well as the apoptosis inducing activity[29] of 1f spurred us to
devise a general and versatile synthetic method. This article described the
first total synthesis of 1e and 1f from readily available starting materials.
RESULTS AND DISCUSSION
The previous synthesis of acerogenin C and/or L employed two different
methodologies. One[30,31] used the SNAr reaction for ether formation and
the acetoacetate ester synthesis for constructing diarylheptanoid skeleton,
whereas the other[32] used the Ullmann reaction and the Wittig reaction,
respectively. Novelty of the present strategy for synthesizing 1e lies in the
preparation of a suitably substituted 1,7-diphenylheptane derivative (6) by a
series of cross-aldol condensation reactions and the formation of a diarylether
bond at the late stage of synthesis via the Ullmann reaction.
The prerequisite 4-benzyloxy-3-methoxycinnamaldehyde (2) was
prepared from commercially available 4-hydroxy-3-methoxybenzaldehyde
in quantitative yield.[34,35] The cross-aldol condensation of 2 with acetone
in the presence of 10% NaOH gave 3 in 93% yield, whereas such condensation
of unprotected 4-hydroxy-3-methoxy-cinnamaldehyde led to much a lower
yield. Catalytic hydrogenation of 3 under an H2 atmosphere at room tempera-
ture for 24 h not only the reduced double bonds but also removed the protect-
ing benzyl group to afford the corresponding 4 in quantitative yield, which was
then subjected to a second aldol condensation reaction with 3-bromo-4-benzy-
loxybenzaldehyde to give the linear diphenylheptenoid 5 in 85% yield. The
catalytic hydrogenation of 6 under an H2 atmosphere for 2.5 h reduced only
the double bond to afford the corresponding compound 6 as pale yellow oil
in 81% yield. It should be noted that the benzyl moiety in compound 6 can
be kept in protection by adjusting the reaction time.
Although several approaches to the formation of biaryl ethers have been
introduced,[36] the Ullmann procedure is the best in some cases.[37] Thus the
[38]
classical Ullmann condition i.e, using CuO/K2CO3
as a catalyst was

Cytotoxic Diarylheptanoids
677
applied to compound 6 to yield the corresponding cyclic diphenylheptanoid,
4-benzylgaleon (7), in 52% yield. The cyclic structure of 7 was confirmed
1
by the characteristic high-field shift of the H-20 resonance in the H NMR
spectrum due to the anisotropic effect of the neighboring orthogonal
benzene ring (dH20 ¼ 5.55 in 7 vs. dH20 ¼ 7.32 in 6). The selective
cleavage of the benzyl ether by catalytic hydrogenation afforded the desired
galeon (1e) in quantitative yield, of which the spectral (1H and 13C NMR as
well as distortionless enhancement by polarization transfer (DEPT), infrared
(IR), and ultraviolet (UV) as well as the physical data were identical to
those reported in the literature.
The O-demethylation of 1e by a previously reported procedure[27]
afforded pterocarine (1f) in 88% yield. The physical and spectral data of the
synthetic substances were identical to those of the natural products.
In conclusion, a simple and practical synthetic procedure for preparing
diphenyl ether-type diarylheptanoid, galeon, was developed using the
Ullmann diaryl ether formation of linear diarylheptanoid, which was
prepared from readily available starting materials via a series of cross-aldol
condensation reactions. Studies on resolving each enantiomer and applying
this method to the synthesis of related diarylheptanoids, acerogenin C and
L, are currently in progress.

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Q. Wang, J.-K. Son, and Y. Jahng
EXPERIMENTAL
Melting points were determined using a Fischer-Jones melting-point apparatus
and are not corrected. IR spectra were obtained using a Perkin-Elmer 1330 spec-
trophotometer. NMR spectra were obtained using a Bruker-(250 spectrometer
250 MHz or 400 MHz for 1H NMR and 62.5 MHz or 100 MHz for 13C
NMR) and are reported as parts per million (ppm) from the internal standard
tetramethylsilane (TMS). Chemicals and solvents were commercial reagent
grade and used without further purification. Electrospray ionization (ESI)
mass spectrometry (MS) experiments were performed on a LCQ advantage-
trap mass spectrometer (Thermo Finnigan, San Jose, CA, USA). Elemental
analyses were taken on a Hewlett-Packard Model 185B elemental analyzer.
All the spectral data of the compounds prepared are consistent with their
structures.
1
6: Colorless oil (83%). IR (KBr) y 3520, 1710 cm21. H NMR (CDCl3,
250 MHz) d 7.57–7.30 (m, 6H), 7.00 (dd, J ¼ 8.2, 2.0 Hz, 1H), 6.80
(d, J ¼ 8.8 Hz, 2H), 6.64 (s, 1H, H20), 6.63 (dd, J ¼ 8.5, 1.5 Hz, 1H), 5.48
(s, 1H, OH, D2O exchangeable), 5.10 (s, 2H, Ph-CH2-), 3.85 (s, 3H, OCH3),
2.78 (t, J ¼ 7.3 Hz, 2H), 2.65 (t, J ¼ 7.0 Hz, 2H), 2.51 (t, J ¼ 7.0 Hz, 2H),
2.40 (t, J ¼ 7.3 Hz, 2H), 1.63–1.51 (m, 4H). 13C NMR (CDCl3, 62.5 MHz)
d 209.78, 153.26, 146.25, 143.54, 136.54, 135.09, 134.05, 133.01, 128.49,
128.22, 127.83, 126.92, 120.77, 114.08, 113.83, 112.27, 110.85, 70.80,
55.78, 44.04, 42.79, 35.33, 31.16, 28.40, 23.27. MS (ESI) calcd. for
C27H29O4Brþ[M þ Hþ] 498, found 498.
7 (4-Benzylgaleon): Pale yellow needles (52%); mp 1138C. IR (KBr) y 1714,
1
1518 cm21. H NMR (CDCl3, 250 MHz) d 7.48 (overlapped d, J ¼ 7.0 Hz,
2H), 7.38–7.27 (m, 3H), 7.03 (d, J ¼ 8.5 Hz, 1H), 6.87–6.84 (m, 2H), 6.76
(d, J ¼ 8.3 Hz, 1H), 6.55 (dd, J ¼ 8.0, 2.0 Hz, 1H), 5.55 (d, J ¼ 1.9 Hz,
1H), 5.38–5.18 (AB quartet, 2H), 3.72 (s, 3H), 2.97 (dd, J ¼ 15.5, 8.2 Hz,
1H), 2.83 (dd, J ¼ 13.0, 5.3 Hz, 1H), 2.71–2.58 (m, 2H), 2.41–2.20
(m, 2H), 2.02 (t, J ¼ 11.6 Hz, 1H), 2.03–1.75 (m, 1H), 1.69–1.50 (m, 4H).
13C NMR (CDCl3, 62.5 MHz) d 210.03, 152.28, 150.23, 145.32, 142.80,
139.67, 137.55, 134.67, 128.43, 127.67, 127.38, 124.25, 122.00, 121.10,
115.66, 115.25, 112.63, 71.68, 56.12, 46.10, 40.97, 36.01, 27.40, 27.03,
19.08. MS (ESI) calcd. for C27H28Oþ4 [M þ Hþ] 417, found 417.
1e (Galeon): White needles (99%); mp 178–1808C (lit.[27] mp 179–1818C,
lit.[28] mp 178–1808C). IR (KBr) y 3387, 1703, 1517 cm21 1H NMR
.
(CDCl3, 250 MHz) d 6.97 (d, J ¼ 8.4 Hz, H18), 6.84 (d, J ¼ 1.9 Hz, H16),
6.83 (d, J ¼ 8.3 Hz, H19), 6.80 (d, J ¼ 8.0 Hz, H5), 6.57 (d, J ¼ 8.3 Hz,
H6), 5.79 (s, OH, D2O exchangeable), 5.53 (d, J ¼ 1.9 Hz, H20), 3.69
(s, 3H, OCH3), 2.94 (dd, J ¼ 16.2, 9.0 Hz, H8A), 2.84–2.55 (m, 3H, 2H14,
H8B), 2.38–2.16 (m, 2H, H9), 2.02–1.85 (m, 1H, H11A), 1.76–1.71 (m, 1H,

Cytotoxic Diarylheptanoids
679
H13A), 1.54–1.49 (m, 4H, H11B, 2H12 & H13B). 13C NMR (CDCl3, 62.5 MHz)
d 210.29 (C55O), 152.07 (C17), 147.21 (C3), 143.04 (C4), 142.70 (C1),
140.03 (C15), 133.20 (C7), 123.95 (C18, CH), 121.94 (C19, CH), 121.86
(C6, CH), 115.00 (C5, CH), 114.91 (C16, CH), 112.18 (C20, CH), 56.00
(OCH3), 46.29 (C11, CH2), 41.25 (C9, CH2), 35.89 (C14, CH2), 27.33
(C13, CH2), 27.25 (C8, CH2), 18.98 (C12, CH2). MS (ESI) calcd. for
C20H22Oþ4 [MþHþ] 327, found 327.
1f (Pterocarine): White powder (88%), mp 1758C. IR (KBr) y 3339, 1696,
1
1590, 1516 cm21. H NMR (CDCl3, 250 MHz) d 6.93 (d, J ¼ 1.6 Hz, H16),
6.87 (d, J ¼ 8.0 Hz, H18), 6.82 (d, J ¼ 8.0, 1.2 Hz, H5), 6.77 (d, J ¼ 8.0 Hz,
H19), 6.62 (d, J ¼ 8.0, 1.0 Hz, H6), 5.62 (br. s, 2H, C4-OH, C17-OH, D2O
exchangeable), 5.54 (d, J ¼ 1.0 Hz, H20), 2.86–2.82 (m, 2H, H8), 2.72–2.65
(m, 2H, 2H14), 2.38–2.16 (m, 2H, H9), 1.89–1.82 (m, 2H, 2H11), 1.67–1.63
(m, 2H, 2H13), 1.58–1.54 (m, 2H12). 13C NMR (CDCl3, 62.5 MHz) d
210.48, 148.76, 146.72, 142.84, 140.63, 140.46, 133.97, 123.36, 122.94,
122.81, 117.81, 115.54, 112.51, 46.46, 41.07, 35.60, 27.26, 27.17, 18.95. MS
(ESI) calcd. for C19H20Oþ4 [MþHþ] 313, found 313.
ACKNOWLEDGMENT
Financial support form Korean Research Foundation Grant KRF-2006-005-
J01101 is gratefully acknowledged. Dedicated to Professor See Ryun Chung
in commemoration of his retirement from Yeungnam University.
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