New synthesis of (S)-dimethyl-4,4′-dimethoxy-5,6,5′,6′- dimethenedioxy-biphenyl-2,2′-dicarboxylate by configuration transform

Article abstract of DOI:10.1016/j.bmcl.2004.01.054

(R/S)-4,4′-Dimethoxy-5,6,5′,6′-dimethenedioxy-2, 2′-di-(4(S)-methyl-oxazoline-1)-biphenyl has been synthesized from dimethyl-4,4′-dimethoxy-5,6,5′,6′-dimethenedioxy-biphenyl-2, 2′-dicarboxylate, and then the diastereoisomer mixture was almost fully converted to a single diastereoisomer with S-configuration ((S)-3) through the key configuration transform promoted by CuI, which was confirmed by CD, HPLC and ¹³C NMR. The C₂-symmetric biphenyl, (S)-dimethyl-4,4′-dimethoxy-5,6,5′,6′-dimethenedioxy-biphenyl- 2,2′-dicarboxylate was prepared easily via the hydrolysis and ester exchange of (S)-3.

Full text of DOI:10.1016/j.bmcl.2004.01.054

Bioorganic & Medicinal Chemistry Letters 14 (2004) 1665–1667
New synthesis of (S)-dimethyl-4,40-dimethoxy-5,6,50,60-
dimethenedioxy-biphenyl-2,20-dicarboxylate by
configuration transform
Sen-Xiang Cheng,a,b Jun-Biao Chang,b Ling-Bo Qua and Rong-Feng Chenb,*
aDepartment of Chemistry, Zhengzhou University, Zhengzhou, Henan 450052, China
bCenter of Research, Henan Academy of Science, Zhengzhou, Henan 450002, China
Received 30 November 2003; accepted 21 January 2004
Abstract—(R/S)-4,40-Dimethoxy-5,6,50,60-dimethenedioxy-2,20-di-(4(S)-methyl-oxazoline-1)-biphenyl has been synthesized from
dimethyl-4,40-dimethoxy-5,6,50,60-dimethenedioxy-biphenyl-2,20-dicarboxylate, and then the diastereoisomer mixture was almost
fully converted to a single diastereoisomer with S-configuration ((S)-3) through the key configuration transform promoted by CuI,
which was confirmed by CD, HPLC and 13C NMR. The C2-symmetric biphenyl, (S)-dimethyl-4,40-dimethoxy-5,6,50,60-dimethene-
dioxy-biphenyl-2,20-dicarboxylate was prepared easily via the hydrolysis and ester exchange of (S)-3.
# 2004 Elsevier Ltd. All rights reserved.
The C2-symmetric biaryl compounds bearing dioxazo-
line,1 diphosphine and other functional groups are
effective ligands for catalytic asymmetric reactions.2
Biaryls from nature exhibit versatile biological activity.
Biaryl compound, schizandrin C from Schizandra chin-
esis (Chinese wuweizi) shows various pharmacological
activities,3 especially anti-heptotoxic activity against
liver injury induced by CCl4. The substrate has been
attracting considerable attention owing to its special
structure and important biological properties. Dime-
thyl-4,40-dimethoxy-5,6,50,60-dimethenedioxy-biphenyl-
2,20-dicarboxylate (ꢀ-DDB, 1), discovered by Xie et al.4
in the course of synthesis of schizandrin C, almost show
the same activity as schizandrin C. It was also demon-
strated that both ꢀ-DDB and some of its derivatives
exhibited anti-HIV activity.5
(S)-DDB was prepared via (S)-4,40-dimethoxy-5,6,50,60-
dimethenedioxy-2,20 -di-(4(S)-methyl-oxazoline-1)-bi-
phenyl ((S)-3) from ꢀ-DDB. Firstly, the key inter-
mediate, (S)-3 was prepared as Scheme 1. ꢀ-DDB was
hydrolyzed to produce a corresponding biphenyl dicar-
boxylic acid, and then it was converted to the biphenyl
dicarboxylic dichloride by the reaction with SOCl2 in
CH2Cl2. The biphenyl dicarboxylic dichloride was
mixed with (S)-2-amino propanol to give biphenyl
dicarboxylic diamide 29 in 81% yield. Compound 2
reacted with SOCl2 to yield corresponding dichloride,
and then (R/S)-310 was obtained in 87% yield by heat-
ing the dichloride in the presence of potassium tert-but-
oxide in the mixed solvent of THF and tert-butanol at
70 ꢀC. HPLC and 13C NMR analysis11 indicated a 50:50
diastereomeric ratio.
The four ortho-substituents of DDB made it difficult to
rotate around aryl–aryl bond, which consequently
resulted in two isomers. And each isomer showed dif-
ferent biological activity.6 To date, there were rarely
report on the preparation of chiral ꢀ-DDB besides
classical resolution of ꢀ-DDB’s racemic isomers.7 In the
present letter, we reported new strategy to prepare
optically pure (S)-DDB through the chiral oxazoline-
mediated configuration transform of the biphenyl.8
Keywords: Asymmetric; Biphenyl; Dioxazoline; CuI.
* Corresponding author. Tel.: +86-3717-763952; fax: +86-3717-
763220; e-mail: lbqu@371.net
0960-894X/$ - see front matter # 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.01.054

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S.-X. Cheng et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1665–1667
ORD curve it was deduced that there was another
positive Cotton effect at the wavelength shorter than
240 nm. The four characteristic Cotton effect at about 305
nm, 293 nm, 260 nm and less than 240 nm corresponded
to a negative–positive–negative–positive in sequence,
and particularly the negative Cotton effect at about 260
nm followed by a positive Cotton effect at wavelength
less than 240 nm can be served as evidence for the S-
configuration of the biphenyl subunit in (S)-3.13 In
addition, it was also proven by the specific rotation.12
Diastereomeric mixture (R/S)-3 was converted to com-
plex (S)-3-Cu as Scheme 2, which was not only owing to
the intramolecularly steric effect between the two
methyls of chiral oxazolines, but also due to the inter-
action between Cu(I) with N atoms of bis-oxazolines.
Complex (S)-3-Cu should dominated over (R)-3-Cu
because there was less spacial repulsion, besides the
distance between Cu(I) and the two N atoms of oxazo-
line rings was shorter in (S)-3-Cu than in (R)-3-Cu,
which prefered to the formation of (S)-3-Cu complex.
Thus, (S)-3 combined with CuI to produce (S)-3-Cu,
and the decrease of (S)-3 led to the equilibrium between
(R)-3 and (S)-3 towards (S)-3 at 80 ꢀC. As a result,
almost all the (R/S)-3 was used to form (S)-3-Cu.
Scheme 1. Reagents and conditions: (a) 1. KOH, 3 equiv in 95%
EtOH, reflux, 4 h; 2. concd HCl ; 3. SOCl2, 3.0 equiv in CH2Cl2, rt,
overnight; 4. (S)-2-aminopropanol 2.2 equiv Et3N, in CH2Cl2, rt, 7 h;
(b) 1. SOCl2 3.0 equiv Et3N; 2. t-BuOK, 2.1 equiv, t-BuOH/THF,
reflux, 8 h; (c) CuI 1.1 equiv, toluene, 80 ꢀC, 20 h.
The mixture of the (R/S)-3 and CuI was heated in dry
toluene under Ar at 80 ꢀC for 20 h. After cooling, the
mixture was washed with 5% aqueous ammonia and
water, and dried with Na2SO4, the solvent was removed
in vacuo, and optically pure (S)-312 was afforded in
97% yield. HPLC and 13C NMR analysis11 indicated
the ratio of diastereomers was 99.5:0.5.
In fact, the aforementioned configuration transform was
different from the transform of the binaphthyl.14 More
important was that the configuration of (S)-3 kept con-
stant at room temperature after the separation of Cu(I)
from the (S)-3-Cu complex. Furthermore, it was also
found that the ratio 50:50 of (S)-3 to (R)-3 held constant
through HPLC and 13C NMR analysis after the dia-
stereomeric mixture (R/S)-3 was heated in DMSO.
The circular dichroism (CD) spectroscopy of (S)-3
exhibited negative Cotton effect at 305 nm and 260 nm,
and positive Cotton effect at 293 nm. On the basis of
Scheme 2.

S.-X. Cheng et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1665–1667
1667
3. Gottlieb, O. R. New Products and Plant Drug with Phar-
macological, Biological or Therapeutical Activity; Springer
Verlag: Berlin Herdelberg, 1977; p227.
4. Xie, J. X.; Zhou, J.; Zhang, C. Z. Scientia Sinica, Series B
1983, 26, 1291.
5. Lee, K. H.; Kashiwada, Y.; Xie, L.; Cosentino, L. M.;
Manak, M.; Xie, J. X.; Cheng, Y. C.; Kilkulskie R. US
5612341, 1997.
6. Institute of Medicine, Chinese Medicinal Academy,
Modern Research of Chinese Herb, 1995, Vol. 1, p385.
7. (a) Zhang, C. Z. Kexue Tongbao 1987, 32, 72. (b) Yeng, F.
W.; Chiu, J. Y.; Wang, C. L. J. US 5 504 221, 1996.
8. Nelson, T. D.; Meyers, A. I. Tetrahedron Lett. 1993, 34,
3061.
9. Biphenyl dicarboxylic amide 2 mp234 ꢀC, [a]D25 ꢁ15.8ꢀ
(c=1.53, CH3OH), 1H NMR (300 MHz, DMSO-d6) d
8.17, 8.14 each (s, 1H, OH), 6.83, 6.78 each (s, 1H, Ar-H),
6.00, 5.84 each (s, 2H, OCH2O), 3.97 (t, 1H, J=7.5,
OCH2), 3.88, 3.87 each (s, 3H, OCH3), 3.74–3.69 (m, 2H,
2NCH), 3.24–3.20 (m, 1H, CH), 3.18–3.12 (m, 1H, CH),
3.10–3.07 (m, 1H, CH), 2.80–2.78 (m, 1H, CH), 0.92 (d,
3H, J=6.6, CH3), 0.80 (d, 3H, J=6.6, CH3); IR 3280,
1616, 1553 cmꢁ1. ESI-MS 505 [M+H]+.
Scheme 3. Reagents and conditions: (a) 1. TFA, 2.5 equiv water 2.2
equiv at rt, overnight. 2. Ac2O 2.2 equiv, DMAP, 0.04 equiv at rt,
overnight; (b) NaOMe, 0.2 equiv in MeOH at rt, overnight.
Secondly, (S)-DDB could be prepared as Scheme 3. (S)-
3 was hydrolyzed in THF with TFA and water and then
the product reacted with acetic anhydride under cata-
lysis of DMAP in pyridine at room temperature, and
the crude diester diamide (S)-4 was afforded. After (S)-4
was alcoholysized in methanol in the presence of
sodium methoxide at room temperature, (S)-dimethyl-
4,40 -dimethoxy-5,6,50,60 -dimethenedioxy-biphenyl-2,20 -
dicarboxylate15 was obtained in 85% yield in two steps.
10. (R/S)-3 mp171–172 ꢀC. 1H NMR (300 MHz, CDCl3) d
7.23 (s, 2H, Ar-H), 5.99 (d, 2H, J=1.2, OCH2O), 5.95 (d,
2H, J=1.2, OCH2O), 4.25–4.15 (m, 4H, oxazoline
OCH2), 3.95 (s, 6H, 2OCH3), 3.77–3.71 (m, 2H, 2NCH),
1.19 (d, 6H, 2CH3); 13C NMR (75 MHz, CDCl3) 163, 147,
142, 136, 121, 111, 109, 101, 73, 61, 56, 21; ESI-MS 469
[M+H]+.
11. HPLC, column ODS C18, MeOH/H2O=55/45, 1 mL/
min, (S)-3: rt=25.7 min, (R)-3: rt=27.6 min. Diaster-
eomeric ratio was also calculated through peak intensity
in 13C NMR.
In summary, we have found an efficient method to
prepare (S)-DDB. (S)-3 was prepared through con-
figuration transform in excellent yield promoted by
interaction between chiral oxazolines moiety of biphenyl
and Cu(I). The stable (S)-3 was conveniently trans-
formed to (S)-DDB. Additionally, the application of
(S)-3 as a chiral ligand of catalytic asymmetric reactions
was under study.
12. (S)-3: mp172–173 ꢀC, [a]D25=ꢁ289ꢀ (c=0.36, in CH2Cl2).
13. (a) Dai, D. C.; Martin, O. R. J. Org. Chem. 1998, 63,
7628. (b) Okuda, T.; Yoshida, T.; Hatano, T.; Koga, T.;
Toh, N.; Kuriyama, K. Tetrahedron Lett. 1982, 23, 3937.
14. Meyers, A. I.; Price, A. J. Org. Chem. 1998, 63, 412.
15. (S)-DDB: [a]D25=ꢁ76.3ꢀ (c=0.36, CH2Cl2). Mp140–
References and notes
1. (a) Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetra-
hedron: Asymmetry 1998, 9, 1. (b) Fu, B.; Du, D. M.
Chinese J. Chem. 2003, 21, 597.
142 ꢀC. H NMR (300 MHz, CDCl3) d 7.43 (s, 2H, ArH),
1
2. Chen, Y. X.; Li, Y. M.; Lam, K. H.; Chan, A. S. C.
Chinese J. Chem. 2001, 19, 794.
6.06 (s, 4H, 2CH2), 4.01 (s, 6H, 2ArOCH3), 3.80 (s, 6H,
2CH3). ESI-MS 419 [M+H]+.