Asymmetric synthesis of β-DDB through oxazoline-mediated Ullmann coupling

Article abstract of DOI:10.1080/00397910500186326

Biphenyl lignan (β-DDB) (2), an effective drug in the treatment of hepatitis, was for the first time asymmetrically synthesized via a chiral oxazoline mediated Ullmann coupling. The two enantiomers of β-DDB have been obtained in this way by using the optically pure amino alcohols L-valinol and D-valinol, respectively. However, attempts to synthesize enantiopure α-DDB (1) by the same method failed because of the racemization of 1 at room temperature in solution. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1080/00397910500186326

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Asymmetric Synthesis of β‐DDB
Through Oxazoline‐Mediated
Ullmann Coupling
Qitao Tan a , Hongyan Li a , Jiwu Wen a , Chen Jiang
a , Xin Wang a & Tianpa You a
a Department of Chemistry , University of Science
and Technology of China , Hefei, Anhui, China
Published online: 18 Aug 2006.
To cite this article: Qitao Tan , Hongyan Li , Jiwu Wen , Chen Jiang , Xin Wang
& Tianpa You (2005) Asymmetric Synthesis of β‐DDB Through Oxazoline‐Mediated
Ullmann Coupling, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 35:17, 2289-2296
To link to this article: http://dx.doi.org/10.1080/00397910500186326
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Synthetic Communicationsw, 35: 2289–2296, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500186326
Asymmetric Synthesis of b-DDB Through
Oxazoline-Mediated Ullmann Coupling
Qitao Tan, Hongyan Li, Jiwu Wen, Chen Jiang, Xin Wang,
and Tianpa You
Department of Chemistry, University of Science and
Technology of China, Hefei, Anhui, China
Abstract: Biphenyl lignan (b-DDB) (2), an effective drug in the treatment of hepatitis,
was for the first time asymmetrically synthesized via a chiral oxazoline mediated
Ullmann coupling. The two enantiomers of b-DDB have been obtained in this way
by using the optically pure amino alcohols L-valinol and D-valinol, respectively.
However, attempts to synthesize enantiopure a-DDB (1) by the same method failed
because of the racemization of 1 at room temperature in solution.
Keywords: Asymmetry, biphenyl diester, bis(oxazoline), coupling, oxazoline
INTRODUCTION
The fruit of Schizandra chinensis has been used as drug in traditional Chinese
medicine for a long time. Several pharmacologically active lignans have been
isolated from the fruit[1–3] and Schizandrin C is the most potent one. The
biphenyl unit in these lignans is crucial for their biological and medical activi-
ties. a-DDB (1), an intermediate formed in the total synthesis of schizandrin
C, has attracted much attention in hepatitis therapy. Furthermore, several of its
derivatives show potent anti-HIV effects.[4] During the total synthesis of
a-DDB, its regioisomer b-DDB (2) was obtained as a by-product.[5,6] The
biphenyl unit of b-DDB is identical to that of schizandrin C and has proved
to be more active than a-DDB in the treatment of hepatitis and for the
Received in Japan April 22, 2005
Address correspondence to Tianpa You, Department of Chemistry, University of
Science and Technology of China, Hefei, Anhui 230026, China. E-mail: ytp@ustc.
edu.cn
2289

2290
Q. Tan et al.
protection against liver damages. Furthermore, it also show potent anti-HIV
effects.[7] Compounds 1 and 2 are chiral molecules because of the rotational
restriction about the biphenyl axis, and they have been resolved by HPLC
method (in the case of 1 also by chemical methods).[8–11] However, no asym-
metric synthesis has been reported so far. We are interested in the pharmaco-
logical effects of the enantiomers of 2 and, therefore, we decided to develop a
practical method for the preparation of enantiopure 2 (Figure 1).
In 1993, Nelson and Meyers[12–14] described a successful stereoselective
Ullmann reaction, which employs a chiral oxazoline as the chiral controller,
and excellent results were obtained. Using this methodology, several enantio-
pure biphenyl bisoxazolines have been successfully prepared that can be
easily transformed into other useful functional groups.[15–17] However, the
amino alcohols used in the synthesis of the chiral oxazolines were all derived
from natural L-amino acids, which led to only one diastereisomer of the chiral
bis(oxazoline) was formed.
Here both L-valinol and D-valinol were used to synthesize the correspond-
ing chiral oxazolines 5a and 5b, followed by asymmetric Ullmann coupling
based on Nelson and Meyers’ method to yield 6a and 6b, which can then
be transformed to (S) and (R)-b-DDB (2) with up to 98% e.e. (Scheme 1).
We chose 3 as the starting material, which was the intermediate in the
total synthesis of racemic 2 from gallic acid.[10] Hydrolysis of 3 afforded 4,
which was then treated with SOCl2 to furnish the corresponding acid chloride.
The latter was treated with L-valinol[18] and Et3N to afford the corresponding
amide alcohol, which was then reacted with SOCl2 followed by reflux with
0.5 M of NaOH in MeOH-H2O to give the oxazoline 5a. While using
D-valinol, 5b was obtained. Treatment of 5a and 5b with activated
copper[19] in refluxing anhydrous DMF for 48 h gave the enantiopure bisoxa-
zoline 6a and 6b, respectively. Compounds 6a and 6b were reacted with tri-
fluoroacetic acid and Na2SO4 followed by acetic anhydride in the presence
of pyridine to provide the ester amides. Transesterification of the latter
Figure 1. 1 (a-DDB) and 2 (b-DDB).

Asymmetric Synthesis of b-DDB
2291
Scheme 1. Reagents and conditions: a) 5% KOH, reflux for 2 h; b) SOCl2; c)
L-valinol or D-valinol, Et3N; d) SOCl2; e) 2% NaOH, MeOH: H2O ¼ 1 : 1, reflux,
2 h; f) activated Cu, DMF, reflux, 40 h; g) TFA, Na2SO4; h) Ac2O, Py; and i)
NaOMe, MeOH, rt, 20 h.
using methanolic NaOMe at rt led to give the corresponding (S)-2 and (R)-2,
respectively.
The e.e. of (S)-2 and (R)-2 was determined by HPLC using a commercial
chiral OD column, and their configuration was assigned according to Ref. 10
Therefore, 6a and 6b are assigned as (S, S, S) and (R, R, R). The results are in
accordance with that described by Nelson and Meyers.[12–14]
We also attempted to synthesize the enantiopure a-DDB (1) by Nelson
and Meyers’ method; however, only racemic 1 was obtained (Scheme 2).
Although high diastereoselectivity (.99% de) has been achieved via asym-
metric Ullmann coupling, unfortunately racemization occurs in the course
of the transformation of the bisoxazoline 8 to the corresponding ester.[20,21]
The racemization may be attributed to the smaller sterical hindrance of the
methylenedioxyl group in 1 than that of the methoxy group in 2, which
leads to easy rotation around the biphenyl axis. To clarify this, the enantio-
pure a-DDB obtained by resolution of racemic a-DDB using enantiopure

2292
Q. Tan et al.
Scheme 2.
a-methylbenzylamine as resolving reagent was dissolved in chloroform or
methanol and complete racemization was observed within 24 h under room
temperature. However, no racemization was observed in the solid state even
when stored at room temperature for several months.
In conclusion, the diasteromerically pure bisoxazolines 6a and 6b have
been successfully synthesized by chiral oxazoline–mediated Ullmann
coupling and transformed to enantiopure b-DDB (2) in up to 98% e.e.
The attempt to synthesize the enantiopure a-DDB (1) failed, although the
corresponding bisoxazoline 8 can be obtained in 99% d.e. using the
same method. Racemization occurs in the course of the transformation of
bisoxazoline 8 to a-DDB (1).
EXPERIMENT
Melting points were recorded on a Thomas-Hoover apparatus and are uncor-
rected. NMR spectra were recorded on Bruker DRX-500 (500 MHz) and
AV-300 (300 MHz) instruments. Elemental analyses were performed on
Vario equipment. Optical rotations were measured on Wzz-1 apparatus. IR
spectra were recorded on a Bruker Equinox55 instrument. Mass spectra
were recorded on Micromass GCT mass spectrometer. The enantiomeric
purities of 2 were assessed by HPLC using a Diacel Chiral OD column. All
the reagents were used as purchased except when stated otherwise.
Compounds 3 and racemic 2 were prepared as reported.[10] L-valinol and
D-valinol were synthesized from L-valine and D-valine.[18]
6-Bromo-7-methoxy-benzo[1,3]dioxole-5-carboxylic acid (4).[7] A suspen-
sion of 3 (24.7 g, 85.4 mmol) in 5% KOH (600 ml) was heated to reflux for 2 h.
The solution was cooled and acidified by hydrochloric acid. The precipitate
formed was collected by filtration, washed with water, and dried at 1008C.
1
4 was obtained as white solid. Yield: 23.0 g (98%). Mp 181–1838C. H
NMR (300 MHz, d6-acetone): d 3.78 (s, 3H), 6.02 (s, 2H), 7.08 (s, 1H).13C
NMR (300 MHz, d6-acetone): 57.1, 101.2, 104.5, 109.5, 125.4, 141.0,
148.5, 152.2, 172.0. Anal. calcd. for C9H10BrO5: C, 39.30; H, 2.57; Found:
C, 39.25; H, 2.55.

Asymmetric Synthesis of b-DDB
2293
(S)-2-(6-Bromo-7-methoxy-benzo[1,3]dioxol-5-yl)-4-isopropyl-4,5-dihydro-
oxazole (5a) and (R)-2-(6-Bromo-7-methoxy-benzo[1,3]dioxol-5-yl)-4-
isopropyl-4,5-dihydro-oxazole (5b). To 8.26 g (30.0 mmol) of 4 was added
SOCl2 (60 ml), and the mixture was heated to reflux for 3 h. After excess
SOCl2 was removed in vacuo, the resulting light-yellow solid was dissolved
in 150 ml of CH2Cl2 and added to a solution of 3.56 g (34.6 mmol) of L-
valinol[18] and Et3N (9.6 ml, 69 mmol) in 120 ml of CH2Cl2 cooled to 08C.
The mixture was stirred overnight, diluted by another 200 ml of CH2Cl2,
then washed with 2 N HCl and brine, and dried (Na2SO4). The solution was
cooled below 08C and then a solution of 8 ml of SOCl2 in 50 ml of CH2Cl2
was added dropwise. The mixture was stirred overnight and again cooled to
08C 10 ml of water and saturated Na2CO3 solution were added. Then, the
solution was separated, dried (Na2SO4), and filtered, and the solvent was
removed in vacuo. The residue was added to 120 ml of MeOH and 4.8 g of
NaOH in 120 ml of water and then heated at reflux for 5 h. After cooling,
MeOH was evaporated and the mixture was extracted with CH2Cl2
(3 ꢀ 100 ml). The CH2Cl2 phase was washed with brine, dried (Na2SO4),
and filtered. Removing the CH2Cl2 gave light-yellow oil, which proved to
be 5a and was pure enough for subsequent use. Yield: 8.27 g, 80%.
[a]2D0 ¼ 240.4 (c 2.0, EtOH). IR (KBr): 1655 (C55N). H NMR (300 MHz,
1
CDCl3): d0.90 (d, J ¼ 6.8 Hz, 3H), 1.0 (d, J ¼ 6.8 Hz, 3H), 1.86 (m, 1H),
3.99 (s, 3H), 4.06–4.15 (m, 2H), 4.39 (m, 1H), 5.99 (s, 2H), 6.86 (s, 1H);
13C NMR (300 MHz, CDCl3): 17.9, 18.5, 32.5, 60.0, 70.3, 72.6, 102.0,
105.3, 108.1, 124.2, 139.2, 140.7, 148.2, 162.6. Anal. calcd. for
C14H16BrNO4: C, 49.14; H, 4.71; N, 4.09; Found: C, 49.10; H, 4.78; N,
4.12. FAB-MS (m/z): 341.
5b: Prepared as 5a from 4. Yield: 77%. [a]2D0 ¼ þ42.08 (c 2.0, EtOH).
Anal. calcd. for C14H16 BrNO4: C, 49.14; H, 4.71; N, 4.09; Found: C,
49.15; H, 4.72; N, 4.11. Spectra are identical to 5b.
(S, S, S)-4,40-Dimethoxy-[5,50]bi[benzo[1,3]dioxolyl]-6,60-bis(4-isopropyl-
4,5-dihydro-oxazole) (6a) and (R, R, R)-4,40-Dimethoxy-[5,50]bi[benzo[1,3]
dioxolyl]-6,60-bis(4-isopropyl-4,5-dihydro-oxazole) (6b). The mixture of
8.27g (24.2 mmol) of the bromo oxazoline 5a, 8.8 g of activated copper
powder,[19] and 18ml of dry DMF was heated to 1108C for 3 h under a
nitrogen atmosphere. Then, additional 50ml of DMF was added and the
mixture was heated to reflux for 48h. After cooling, the mixture was diluted
with 300 ml of CH2Cl2 and washed with 5% aqueous ammonia (3 ꢀ 150 ml)
and brine (2 ꢀ 100 ml), and dried (Na2SO4). After the solvent was removed,
the residue was subjected to column chromatography (petroleum ether–
EtOAc ¼ 5 : 1, neutral Al2O3) to give a light-yellow solid. After it was recrys-
tallized from petroleum ether (50 ml) and EtOAc (5 ml), 3.88g of diastereo-
merically pure bis(oxazoline) 6a was obtained as a white needle crystal.
Yield: 65%. Mp 108–1118C; [a]2D0 ¼ 270.3 (c 0.8, EtOH). 1H NMR
(300 MHz, CDCl3): d 0.75 (d, J ¼ 6.8 Hz, 6 H), 0.84 (d, J ¼ 6.8 Hz, 6H),

2294
Q. Tan et al.
1.55–1.62 (m, 2H), 3.76 (s, 6H), 3.64–3.84 (m, 4H), 4.06 (m, 2H), 5.99 (s, 4H),
7.10 (s, 2H). 13C NMR (300MHz, CDCl3): 18.3, 18.8, 32.8, 59.8, 70.2, 72.6,
101.5, 104.0, 122.5, 125.3, 138.8, 141.5, 148.2, 163.2. IR (KBr):
1652cm21(C55N). Anal. calcd. for C28H32N2O8: C, 64.11; H, 6.15; N, 5.34;
Found: C, 64.08; H, 6.18; N, 5.32. FAB-MS (m/z): 524.
6b: Prepared as 6a from 5b. Yield: 62%.Mp 105–1078C. [a]2D0 ¼ þ 68.8
(c 1.2, EtOH). 1H NMR (300 MHz, CDCl3): d 0.75 (d, J ¼ 6.8 Hz, 6H), 0.82
(d, J ¼ 6.8 Hz, 6H), 1.55–1.62 (m, 2H), 3.78 (s, 6H), 3.58–3.76 (m, 4H),
4.09(m, 2H), 6.01(s, 4H),7.15 (s, 2H); 13C NMR (300 MHz, CDCl3): 18.3,
18.9, 31.8, 59.8, 71.2, 72.2, 101.8, 104.2, 122.6, 125.7, 138.9, 141.7, 148.3,
163.5; IR (KBr): 1652 cm21 (C55N); Anal. calcd. for C28H32N2O8:
C, 64.11; H, 6.15; N, 5.34; Found: C, 64.18; H, 6.15; N, 5.37. FAB-MS
(m/z): 524.
(S)-4,40-Dimethoxy-[5,50]bi[benzo[1,3]dioxolyl]-6,60-dicarboxylic acid
dimethyl ester (S-2) and (R)-4,40-Dimethoxy-[5,50]bi[benzo[1,3]dioxolyl]-
6,60-dicarboxylic acid dimethyl ester (R-2). To the bis(oxazoline) 6a
(2.0 g, 3.8 mmol) was added THF (200 ml), H2O (4.5 ml), trifluoroacetic
acid (6.0 ml, 78.4 mmol), and Na2SO4 (20 g). The mixture was stirred vigor-
ously overnight. Additional Na2SO4 was added to ensure anhydrous con-
ditions and then the solvent was removed below 458C. The resultant
colorless liquid was added to 150 ml of CH2Cl2, 10 ml of Ac2O, and 10 ml
of pyridine. The reaction was stirred at rt for 2 days. Then the mixture was
diluted to 300 ml, washed with 2 N of HCl (3 ꢀ 100 ml) and brine
(2 ꢀ 100 ml) and dried (Na2SO4). After removing the solvent, a white solid
was obtained. To the solid was added an NaOMe solution prepared by the
dissolution of sodium (3.0 g, 13 mmol) in methanol (120 ml). After stirring
at rt for 5 h, a white precipitation formed. The mixture was neutralized with
methanolic acetic acid and the solvent was removed by rotary evaporation.
The residue was added to 100 ml of water and extracted with CH2Cl2
(2 ꢀ 80 ml). The extraction was washed with brine and dried (Na2SO4).
After removal of the solvent, the residue was purified by silica-gel chromato-
graphy with petroleum ether–EtOAc–CH2Cl2 (7 : 2 : 1) as eluent to give 2 as
a white solid, 1.2 g, 75.5%. Mp 206–2088C (lit.[10] 207–2088C); [a]2D0
¼
242.28 (c 1.2, CHCl3); e.e. ¼ 96.5%. Chiral HPLC analysis: chiral OD
column, 1.0 ml/min, 8 : 2 hexane–isopropanol, l ¼ 254 nm, tR(S) ¼ 21.2min;
1H NMR(300 MHz, d6-acetone) d 3.56(s, 3H), 3.71 (s, 3H), 6.15 (s, 4H),
7.12 (s, 2H).
R-2: Prepared from 6b as S-2. Yield: 69%. Mp 206–2078C (lit.[10] 207–
2088C); [a]2D0 ¼ þ43.28 (c 1.5, CHCl3). E.e. (98%). Chiral HPLC analysis: tR
(R) ¼ 11.2 min. Spectra are identical to S-2.
The resolution of a-DDB (1) and research on the racemization of
enantiopure 1. A suspension of 8.36 g (20 mmol) of 1 was hydrolyzed to
its diacid according to Ref. 22 and then the diacid was suspended in 50 ml

Asymmetric Synthesis of b-DDB
2295
of EtOH and 6 ml of H2O, heated to 608C and 5 ml (40.0 mmol) of L-(2)-a-
benzylethyl amine in 10 ml of EtOH was added. After the addition, the
mixture turned clear and was cooled to rt, and a colorless crystal formed
gradually overnight. The crystals were collected, washed with EtOH, and
recrystallized from EtOH twice yielding 4.1 g of colorless crystals. The
crystals were dissolved in 30 ml of H2O and the solution was acidified with
HCl. A white solid precipitated immediately, which was collected by filtration
and washed with water. The optically active biphenyl dicarboxylic acid was
obtained with [a]D20 ¼ 283 (c 1.5, C5H5N) and mp 2638C (lit.[8] 260–
2628C). The acid was dissolved in saturated Na2CO3 and 2.0 ml of dimethyl
sulfate was added. A white solid formed immediately and the mixture was
stirred for 1 h. The solid was filtered and washed with water to give 1.5 g of
(2)-a-DDB 1. [a]D20 ¼ 281(c 0.5, CHCl3) [lit.[8] [a]2D1 ¼ 278.60 (c 0.52,
CHCl3)]. Mp178–1798C (lit.[5] 179–1818C); e.e. ¼ 95%. The e.e. was
assessed by HPLC method: chiral OD column, 1.0 ml/min, 8 : 2 hexane–
1
isopropanol, l ¼ 254 nm. H NMR (300 MHz, CDCl3):d 3.67 (s, 6H), 3.96
(s, 6H), 5.99 (s, 4H), 7.37 (s, 2H).
Racemization of (2)-a-DDB 1 in CHCl3 has also been studied. A
solution of (2)-a-DDB 1 in CHCl3 with a rotation [a]2D0 ¼ 281 (c 0.5,
CHCl3) was put at 208C. After 28 h the rotation turned to 0. The racemization
in other solvents such as methanol was also observed. However, in the solid
form no racemization has occurred when stored for several months.
ACKNOWLEDGMENT
We are grateful to the Natural Science Foundation of Anhui Province of China
for financial support.
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