BULLETIN OF THE
Article
Synthesis and Biological Activity of Phenylbutenoid Dimers
KOREAN CHEMICAL SOCIETY
intermediates (7A0–C0 and 7E0–H0) were prepared following
the same reaction conditions from the corresponding alcohols,
respectively. Analytical data of other compounds are available
as Supporting Information.
the butadienes 4A–G, acrolein, and catalytic amount of BF3-
Et2O.6–9 The stereochemistry of two chiral centers in cyclo-
hexene ring of 5A–G was identified as cis based on the chem-
ical shift values of two protons on chiral carbons (H-3, 2.73
ppm; H-4, 3.90 ppm) by comparing the chemical shift data
in 1H NMR spectra from precedent literatures.5a,b We found
that cis cyclohexene intermediates possessed different chem-
ical shift values of two protons on chiral carbons (H-3, 2.73
ppm/H-4, 3.92 ppm5a and H-3, 2.74 ppm/H-4, 3.91 ppm5b)
compared with those of the trans cyclohexene intermediate
(H-3, 2.58 ppm; H-4, 3.71 ppm).5b Ylides (7A0–H0) were pre-
pared from the corresponding aldehydes in two steps. Reduc-
tion of aldehydes with sodium borohydride in methanol
(93–100%) followed by reactions with Ph3PꢀHBr and n-BuLi
in toluene (70–94%) gave ylides (7A0–H0). Reactions in
Schlosser conditions10 between aldehydes 5A–G and ylides
7A0–H0 yielded PBD analogs 8a–p (40–55%) with E-stereo-
chemistry. The stereochemistry of the double bond was
decided as “E” based on the coupling constant (J = 16 Hz)
of twovinyl protons. The stereochemistry of twochiral centers
of synthesized PBD analogs 8a–8p was identified as trans
based on the chemical shift values and the large chemical shift
difference of twoprotons onchiral carbons(H-3, 3.16 ppm;H-
4, 2.24 ppm). By comparing the chemical shifts in 1H NMR
spectra from precedent literatures,5a,b we found that trans
PBDanalogs possesseddifferent chemicalshift valuesandrel-
atively large chemical shift difference of two protons on chiral
carbons (H-3, 3.18 ppm/H-4, 2.35 ppm5a and H-3, 3.16 ppm/
H-4, 2.14 ppm5b) compared with those of the cis PBD analog
(H-3, 3.52 ppm/H-4, 2.80 ppm).5a Our results imply that
the “cis” stereochemistry of aldehydes 5A–G seemed to be
changed to trans during olefination reaction in strong base
(n-BuLi). Thus, we successfully synthesized 16 PBD analogs
with E and trans stereochemistry without any further elabora-
tion from cis cyclohexene intermediates.
Typical Procedures for the Preparation of PBDs 8a–p. To
a solution of compound 7D0 (0.59 g, 1.2 mmol) in toluene (10
mL) was slowly added n-BuLi (0.48 mL, 2.5 M in hexane) at
−20 ꢁC. The solution was stirred for 30 min at this tempera-
ture, then the compound 4A (0.23 g, 1.0 mmol) in toluene
(5 mL) was slowly added. The reaction mixture was heated
to reflux and stirred for 3 h, quenched with saturated aqueous
NH4Cl (5 mL), extracted with ethyl acetate (2 × 50 mL),
washed with saturated NaHCO3 (20 mL) and brine (20 mL),
dried over MgSO4, filtered and evaporated. The residue was
purified by column chromatography (hexane:Acetone, 5:1)
to afford compound 8a (1, 0.14 g, 41%) as a light yellow
oil. 1H NMR (400 MHz, CDCl3): δ 6.75–6.84 (m, 4H),
6.66–6.71 (m, 2H), 6.10 (d, J = 16 Hz, 1H), 6.03 (dd, J = 16
Hz, 6.8 Hz, 1H), 5.90 (m, 1H), 5.67 (m, 1H), 3.81–3.88 (s,
3H × 3), 3.16 (m, 1H), 2.24 (m, 1H), 2.21 (m, 2H), 1.92 (m,
1H), 1.69 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 149.4,
148.7, 146.6, 144.3, 137.3, 132.6, 131.4, 130.7, 129.3, 127.9,
121.6, 119.2, 114.3, 111.6, 111.4, 109.2, 56.3, 56.3, 56.2,
48.5, 45.8, 28.2, 24.9. MS for C23H26NaO4 (MALDI-TOF):
[M + Na]+ 389.19. Other compounds (8b–8p) were prepared
following the same reaction conditions from the corresponding
intermediates,respectively.Analyticaldataofothercompounds
(8b–8p) are available as Supporting Information.
Results and Discussion
Synthesis. PBD analogs (8a–p) were synthesized following a
concise synthetic route outlined in Scheme 1. Zinc-mediated
allylation of aldehydes yielded the corresponding alcohols
3A–G (90–95%). Dehydration of the alcohols in the presence
of p-toluenesulfonic acid gave the corresponding butadienes
4A–G (46–75%). Cyclohexenecarbaldehydes (5A–G), key
intermediatesfor Diels–Alder reaction, were synthesized from
NO and TNF-α Assay. Inhibitions of iNOS-mediated NO
production and TNF-α release by synthetic PBD analogs were
determined in LPS-stimulated RAW 264.7 cells.11 Briefly,
H
O
H
C O
H
O C
R1
5A-5G
a
c
b
R1
R1
ring-A
R1
4A-4G
3A-3G
f
R2
H
C O
r
PPh3B
H
O
e
R1
8a-8p
d
R2
R2
R2
ring-B
6A'-6H'
7A'-7H'
(A=3-OCH3, 4-OH; B=4-OH; C=3-OCH3; D=4-H; E=3,5-(OCH3)2, 4-OH; F=3-OCH3, 4-F; G=3,5-(OCH3)2)
(A'=4-OCH3 ; B'=4-H; C'=3,4,5-(OCH3)3; D'=3,4-(OCH3)2; E'=4-CH3; F'=4-Cl; G'=3,4-Cl2; H'=3-OCH3)
Scheme 1. Synthesis of PBD analogs. Reagents and conditions: (a) allyl bromide, Zn, aqueous NH4Cl–THF (5:1), 0 ꢁC, 2 h, 90–95%; (b) TsOH,
reflux, 2–3 h, 46–75%; (c) acrolein, BF3-Et2O, 55–80%; (d) NaBH4, MeOH, 0 ꢁC, 4 h, 93–100%; (e) Ph3PꢀHBr, CH3CN, reflux, overnight,
70–94%; (f ) n-BuLi, toluene, −20 ꢁC ! reflux, 3 h, 40–55%.
Bull. Korean Chem. Soc. 2015, Vol. 36, 1676–1680
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim