Total synthesis of 4″O-acetylmananthoside B, Part I: Synthesis and tentative ozonolysis of a cyclohexadiene derivative

Article abstract of DOI:10.1080/00397910600948104

A cyclohexadiene derivative cis-N,N-diethyl-2-benzyloxymethyl-1,2- dihydrobenzamide 8 was constructed from γ-butyrolactone I for the total synthesis of a natural product 4″-O-acetylmananthoside B, which was reported to display significant cytotoxic activity. Preliminary ozonolysis of 8 for further synthetic purposes was also carried out. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600948104

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Total Synthesis of 4″‐O‐Acetylmananthoside
B, Part I: Synthesis and Tentative Ozonolysis
of a Cyclohexadiene Derivative
Guilong Zhao a , Jiong Jia a , Junzhi Liu a & Jianwu Wang a
a School of Chemistry and Chemical Engineering, Shandong University, Jinan,
China
Version of record first published: 01 Dec 2006.
To cite this article: Guilong Zhao , Jiong Jia , Junzhi Liu & Jianwu Wang (2006): Total Synthesis of
4″‐O‐Acetylmananthoside B, Part I: Synthesis and Tentative Ozonolysis of a Cyclohexadiene Derivative,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
36:24, 3821-3828
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Synthetic Communicationsw, 36: 3821–3828, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600948104
Total Synthesis of 400-O-Acetylmananthoside
B, Part I: Synthesis and Tentative
Ozonolysis of a Cyclohexadiene Derivative
Guilong Zhao, Jiong Jia, Junzhi Liu, and Jianwu Wang
School of Chemistry and Chemical Engineering, Shandong University,
Jinan, China
Abstract: A cyclohexadiene derivative cis-N,N-diethyl-2-benzyloxymethyl-1,2-dihy-
drobenzamide 8 was constructed from g-butyrolactone I for the total synthesis of a
natural product 400-O-acetylmananthoside B, which was reported to display significant
cytotoxic activity. Preliminary ozonolysis of 8 for further synthetic purposes was also
carried out.
Keywords: Cyclohexadiene, Diels–Alder reaction, ozonolysis, total synthesis
INTRODUCTION
Susplugas and coworkers[1] reported 400-O-acetylmananthoside B, which was
isolated from the leaves and stems of Justicia patentaflora in Vietnam and
reported to display significant cytotoxicity (Fig. 1); however, mananthoside
B, possessing an almost identical molecular skeleton, was first disclosed by
Chen and coworkers[2] and also demonstrated cytotoxicity.
Encouraged by the potent cytotoxicity displayed by this variety of
compounds and the challenging work involved in the building of this kind
of new molecular framework, we decided to carry out the total synthesis of
400-O-acetylmananthoside B and report the synthesis of cis-N,N-diethyl-2-ben-
zyloxymethyl-1,2-dihydrobenzamide 8 as part of our work.
Received in Japan April 10, 2006
Address correspondence to Jianwu Wang, School of Chemistry and Chemical
Engineering, Shandong University, Jinan 250100, China. E-mail: zhao_guilong@
sohu.com
3821

3822
G. Zhao et al.
Figure 1. Molecular structure of 400-O-acetylmananthoside B and mananthoside B.
RESULTS AND DISCUSSION
The retrosynthetic analysis of the target molecule 400-O-acetylmananthoside B
is outlined in Scheme 1, and as shown there, it can be divided into three
fragments, I, II, and III. We herein focus the partial construction of
fragment II.
In view of the susceptibility of the lactone functionality in II to a wide
range of reagents and conditions involved in the course of the creation of
II, we devised a synthetic strategy to mask the susceptible lactone functiona-
lity (conversion of the lactone functionality into a tertiary amide and an ortho-
substituted benzyloxymethyl group) (Scheme 2). Thus, we herein describe the
synthesis of a cyclohexadiene derivative cis-N,N-dimethyl-2-benzyloxy-
methyl-1,2-dihydrobenzamide 8, which is an important synthon for the
building of II (Scheme 2).
Scheme 1. Retrosynthetic analysis for 400-O-acetylmananthoside B.

400-O-Acetylmananthoside B
3823
Scheme 2. Cyclohexadiene derivative 8 is an important synthon of II.
The synthesis of 8 has the advantage of g-butyrolactone 1 as a starting
material, and the final synthetic approach is illustrated in Scheme 3.
The synthesis of dienophile 3 was achieved from commercially available
g-butyrolactone 1 using a known procedure with some modifications.[3]
A Diels–Alder to construct the bicyclic lactone 4 was then successfully
carried out utilizing 3 as dienophile and 1,3-butadiene as diene in a sealed
vessel at 1508C for 12 h. Because 1,3-butadiene is a gas at ambient temp-
erature and because the reaction must be carried out at a high temperature,
1,3-butadiene was liquefied by cooling to 2358C, and the Teflonw reaction
vessel containing the dienophile 3 in toluene was cooled to 2108C before
the liquefied 1,3-butadiene was added in the vessel coated with stainless
steel. The vessel was then sealed and heated at 1508C; no emission was
detected. Attempts to carry out this reaction using Lewis acids[4–6] (such as
aluminum chloride, titanium chloride, and zinc chloride) as catalysts failed.
Reaction of 4 with bromine in methylene chloride at ambient temperature
proceeded smoothly to furnish a bromide, which underwent dehydrobro-
mination in refluxing toluene in the presence of 1,8-diazobicyclo[5,4,0]-
undec-7-ene (DBU), and gave an aromatic lactone 100 after careful
spectroscopic analyses, rather than the desired diene 10, which was previously
expected to be an equivalent to 8 (Scheme 4). There is no doubt that the
Scheme 3. Synthetic approach to 8, reagents and conditions: (a) (1) Br2/P, (2) H2O,
reflux; (b) Et3N/PhH, reflux; (c) 1,3-butadiene/PhMe, sealed vessel, 1508C; (d)
Et2NH/PhMe, sealed vessel, 1508C; (e) (1) NaH/THF, (2) BnBr/Kl; (f) Br2/
CH2Cl2; and (g) DBU/PhMe, reflux.

3824
G. Zhao et al.
Scheme 4. Unsuccessful synthetic approach to 10.
generation of 100 was through a tribromide 90, although it was never isolated.
An attempt to suppress the generation of 90 by performing the bromination of 4
at 2908C was unsuccessful; it also produced 100 rather than the desired 10
after the dehydrobromination procedure described previously.
Consequently, we devised a strategy to protect the lactone functionality.
Aminolysis of 4 followed by benzylation converted 4 into 6. The tertiary
amide together with the benzyloxymethyl group at its ortho portion can
function as a masked lactone functionality (Scheme 5), and near the end of the
total synthesis, this lactone can be readily liberated after hydrolysis to convert
the amide into the carboxylic acid and hydrogenated to remove the benzyl group.
Compound 6 (masked lactone 4) was converted into a diene 8 after
bromination in methylene chloride at ambient temperature and subsequent
dehydrobromination in refluxing toluene in the presence of DBU.
Tentative ozonolysis of 8 was also carried out, giving a dialdehyde 11 by
cleavage of one of the two C55C double bonds (Scheme 6), which was not the
desired product 110 initially expected to be obtained by cleavage of the two
C55C double bonds. Which of the two C55C double bonds was cleaved was
determined by NMR spectroscopy. Further investigations to obtain the
desired product 110 are in progress.
EXPERIMENTAL
The IR spectra were recorded on a Thermo Nicolet Avtar FT370 spectropho-
1
tometer as thin film. The H NMR and 13C NMR spectra were all obtained
Scheme 5. Strategy to protect the lactone functionality.

400-O-Acetylmananthoside B
3825
Scheme 6. Ozonolysis of diene 8 produces 11 by cleavage of one of the two C55C
double bonds.
from a Bruker Avance 400 spectrometer employing CDCl3 as solvent and
TMS as internal standard. The ESI-MS spectra were recorded on an ABI
API 4000 mass spectrometer using electrospray ionization. The GC-MS and
the high-resolution (TOF) analyses were carried out on a Waters GCP high-
resolution mass spectrometer. Elemental analyses were performed with an
Elementar EI Vario III CHN analyzer.
Procedure for the Synthesis of cis-2-Hydroxymethyl-1,2,3,5-
tetrahydrobenzoic Acid Lactone (4)
A 25-mL Teflonw cylinder coated with stainless steel was charged with
4.0 g (47.6 mmol) of 2(5H)-furanone 3 and 6 mL of dried toluene and
cooled to 2108C by means of keeping it refrigerated for around 1 h
before the addition of 10 mL of liquefied 1,3-butadiene (ca. 148 mmol),
which was obtained by introducing gaseous 1,3-butadiene into a 100-mL
flask immersed in an ethanol bath at 2358C. About 50 mg of hydroquinone
was added to prevent the polymerization of butadiene in the reaction. The
cylinder was sealed and heated in a hot furnace at 1508C for 12 h.
The hot cylinder was cooled to ambient temperature spontaneously and
then to 2108C before it was opened. The resulting mixture was poured into
40 mL of acetone, and the obtained slurry was filtered. The filtrate was concen-
trated on a rotary evaporator and subjected to column chromatography to afford
4 as colorless oil: 5.4 g, 82%. IR (thin film), n 3031 (m, 55C–H), 1773 (vs,
1
C55O), 1659 (w, C55C), 1135 (s, C–O) cm21. H NMR (CDCl3, 400 MHz):
d 5.69 (m, 2H), 4.25–4.29 (dd, 1H, J ¼ 5.2 Hz, J ¼ 8.8 Hz), 3.96–3.98 (dd,
1H, J ¼ 2.0 Hz, J ¼ 8.8 Hz), 2.71–2.76 (ddd, 1H, J ¼ 2.7 Hz, J ¼ 7.9 Hz),
2.55–2.62 (m, 1H), 2.43–2.47 (d, 1H, J ¼ 17.3 Hz), 2.30–2.37 (dd, 1H,
J ¼ 8.5 Hz), 2.20–2.26 (dd, 1H, J ¼ 7.1 Hz, J ¼ 16.2 Hz), 1.81–1.88
(m, 1H). 13C NMR (CDCl3, 100 MHz), d 178.61, 124.59, 124.38, 72.27,

3826
G. Zhao et al.
36.74, 31.44, 24.18, 21.49. GC-MS, m/z ¼ 138 (Mþ), HR-TOF-MS, Mþ ¼
138.0667; required for C8H10O2, 138.0681. Elemental analysis calcd. for
C8H10O2, C, 69.55; H, 7.30; found, C, 69.60; H, 7.32.
Procedure for the Synthesis of cis-N,N-Diethyl-o-hydroxymethyl-
1,2,3,6-tetrahydrobenzamide (5)
Compound 4 (5.0 g, 36 mmol) and 20 mL of diethylamine was dissolved
in 30 mL of dried toluene, and the resultant mixture was introduced into a
75-mL Teflonw cylinder coated with stainless steel. The cylinder was sub-
sequently sealed and heated at 1508C for 12 h.
On cooling to ambient temperature, the cylinder was opened, and the
reacting system was evaporated on a rotary evaporator to remove toluene
and the excess diethylamine. The residue thus obtained was subjected to
column chromatography to provide the product as colorless viscous oil:
7.2 g, 95%. IR (thin film), n 3412 (vs, OH), 3023 (m, 55C–H), 1616 (vs,
1
C55O), 1065, 1255 (C–O, C–N) cm21. H NMR (CDCl3, 400 MHz): d
5.65 (m, 2H), 3.46–3.51 (m, 2H), 3.24–3.44 (m, 4H), 2.77 (bs, 1H), 2.57–
2.64 (m, 1H), 2.04–2.27 (m, 4H), 1.18–1.93 (m, 1H), 1.06–1.10, 1.14–
1.17 (t þ t, 3H each, J ¼ 7.1 Hz). 13C NMR (CDCl3, 100 MHz), d 174.87,
125.70, 124.76, 65.41, 37.72, 39.06, 40.19, 41.72, 27.65, 29.54, 12.56,
14.47. GC-MS, m/z ¼ 211 (Mþ), HR-TOF-MS, Mþ ¼ 211.1582; required
for C12H21NO2, 211.1572. Elemental analysis calcd. for C12H21NO2, C,
68.21, H, 10.02; N, 6.63; found, C, 68.16; H, 10.00; N 6.61.
Procedure for the Synthesis of cis-N,N-Diethyl-o-benzyloxymethyl-
1,2,3,6-tetrahydrobenzamide (6)
Compound 5 (0.86 g, 4.08 mmol) and 10 mg of dried potassium iodide were
dissolved in 10 mL of dried THF, and the resulting mixture was stirred for half
an hour. Subsequently, 0.171 g (5 mmol, 70%) of sodium hydride was added
with care to the solution, which was cooled with ice-water bath, and the
mixture was then stirred until there was no evolution of gas. Benzyl
bromide (0.855 g, 5 mmol) was added dropwise, and the resultant mixture
was then stirred at room temperature for another 4 h until the completion of
the reaction as monitored by thin-layer chromatography (TLC).
The solid was removed by filtration, and the filtrate was evaporated on a
rotary evaporator to give a residue, which underwent column chromatography
to yield the desired product as a colorless heavy oil: 1.36 g, 93%. IR (thin
film), n 3063 (w, Ar-H), 3025 (m, 55C–H), 1634 (vs, C55O), 1453, 1481
(m, skeleton of benzene ring), 1379 (m, Me), 1252, 1219 (m, C–O), 1074,
1
1109 (m, C–N). H NMR (CDCl3, 400 MHz): d 7.32–7.42 (m, 5H), 5.77
(m, 2H), 4.51 (s, 2H), 3.58–3.65 (m, 2H), 3.53–3.56 (dd, 1H, J ¼ 3.8 Hz,
J ¼ 9.3 Hz), 3.45–3.48 (dd, 1H, J ¼ 2.0 Hz, J ¼ 9.3 Hz), 3.19–3.32

400-O-Acetylmananthoside B
3827
(m, 2H), 2.86–2.92 (m, 1H), 2.15–2.48 (m, 5H), 1.16–1.20 (t, 6H,
J ¼ 7.1 Hz). 13C NMR (CDCl3, 100 MHz), d 174.30, 138.12, 127.77,
127.04, 126.93, 126.01, 124.82, 72.64, 71.75, 41.62, 40.07, 37.49, 36.11,
29.49, 27.76, 14.45, 12.77. GC-MS, m/z ¼ 301 (Mþ), HR-TOF-MS,
Mþ ¼ 301.2043, required for C19H27NO2, 301.2042. Elemental analysis
calcd. for C19H27NO2, C, 75.71; H, 9.03; N, 4.65; found, C, 75.79; H, 9.00;
N 4.67.
Procedure for the Synthesis of cis-N,N-Diethyl-o-benzyloxymethyl-
1,2-dihydrobenzamide (8)
A 50-mL, three-necked, round-bottomed flask was charged with 0.602 g
(2 mmol) of 6 and 10 mL of methylene chloride, and while shaking,
bromine was added until the brown color persisted for at least half an hour
at ambient temperature, when TLC analysis indicated that there was no
reactant 6 left. The mixture was subsequently evaporated on a rotary evapor-
ator to afford a residue, and about 50 mL of toluene was added into the flask,
followed by addition of 1 mL (6.6 mmol) of DBU. The mixture thus obtained
was then refluxed for around 7 h until the complete consumption of the inter-
mediate dibromide 7.
Upon cooling, the slurry mixture was dilute with 30 mL of diethyl ether
and filtered to remove the insoluble salt. The filtrate was transferred into
a separatory funnel, washed successively with dilute hydrochloric acid
and water, and dried with anhydrous sodium sulfate. Evaporation of
solvents on a rotary evaporator afforded a residue, which was purified by
careful column chromatography to yield the product as pale yellow oil:
0.47 g, 78%. IR (thin film), n 3087, 3061, 3035 (w, Ar-H), 1455, 1495,
1499, 1584 (m, skeleton of benzene ring), 1616 (vs, C55O), 1363, 1381
1
(m, Me), 1283, 1099 (s, C–O, C–N). H NMR (CDCl3, 400 MHz): d 7.25–
7.33 (m, 5H), 5.96–5.97, 5.90–5.93, 5.82–5.85 (m þ m þ m, 1H each),
4.45–4.46 (d, 2H), 3.53–3.62 (m, 2H), 3.44–3.48, 3.28–3.31 (m þ m, 2H
each), 2.91–2.93 (m, 1H), 2.43–2.48 (mm, 1H each), 1.09–1.12 (t, 6H,
J ¼ 7.1 Hz). 13C NMR (CDCl3, 100 MHz), d 170.89, 138.04, 127.76, 127.03,
126.93, 133.25, 127.85, 127.13, 126.81, 123.01, 122.26, 72.39, 69.57, 34.08,
25.03. GC-MS, m/z ¼ 299 (Mþ), HR-TOF-MS, Mþ ¼ 299.1878; required
for C19H25NO2, 299.1885. Elemental analysis calcd. for C19H25NO2, C,
76.22; H, 8.42; N, 4.68; found, C, 76.11; H, 8.45; N, 4.65.
Procedure for the Ozonolysis of 8 to Produce (S)-N,N-Diethyl-2-(S-
1-benzyloxymethyl-2-oxo-ethyl)-5-oxo-3-pentenamide (11)
A three-necked, round-bottomed flask was charged with 2.0 g (6.7 mmol) of 8
and 15 mL of dried methylene chloride, and the flask containing the mixture
was immersed into a mixture of crushed ice and calcium chloride (2208C).

3828
G. Zhao et al.
With stirring, the ozone produced by an ozone-initiator was bubbled into the
cooled solution until the yellow color persisted.
Subsequently, 1.5 mL of dimethylsulfide was added dropwise, and the
mixture was stirred at ambient temperature for another 12 h, when the mixture
turned dark brown. The mixture was transferred into a separatory funnel,
washed with 100 mL of brine in two portions, and dried over anhydrous
sodium sulfate. Evaporation of the solvent on a rotary evaporator below 458C
furnished a dark brown oil, which was chromatographed on silica gel to give
rise to the pure product as colorless oil. The pure product was kept at a flask
masked with black paper and stored in refrigerator below 2108C: 1.7 g, 75%.
IR (thin film), n 3030, 3063 (w, Ar-H), 2731 (w, C-H in formyl group), 1722
(s, C55O linked to the saturated carbon), 1677 (s, C55O linked to the sp2-hybri-
dized carbon), 1627 (s, C55O in amide functionality), 1455, 1474, 1496
(m, skeleton vibration of the benzene ring), 1364, 1384 (Me), 1127, 1101
1
(s, C–O). H NMR (CDCl3, 400 MHz): d 10.16–10.18 (d, 1H, J ¼ 7.2 Hz),
9.75 (s, 1H), 7.25–7.33 (m, 5H), 5.90–5.92 (d, 1H, J ¼ 7.1 Hz), 4.49
(s, 2H), 4.22–4.25 (m, 1H), 3.58–3.63 (m, 2H), 3.13–3.18, 3.34–3.43
(m þ m, 1H þ 3H), 2.97–3.03 (dd, 1H, J ¼ 7.1 Hz, J ¼ 18.5 Hz), 2.75–2.81
(dd, 1H, J ¼ 5.4 Hz, J ¼ 18.5 Hz), 1.07–1.26 (m, 6H). 13C NMR (CDCl3,
100 MHz), d 199.27, 190.16, 167.66, 153.43, 136.97, 128.07, 127.95,
127.36, 127.16, 72.80, 71.31, 44.15, 42.25, 38.05, 38.58, 13.29, 12.00.
ESI-MS, m/z ¼ 332.6 (M þ 1). Elemental analysis calcd. for C19H25NO4,
C, 68.86; H, 7.60; N, 4.23; found, C, 68.71; H, 7.63; N, 4.22.
ACKNOWLEDGMENT
The authors express sincere gratitude to Guiyun Duan and Datong Zhang for
their valuable discussions.
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