Asymmetric biomimetic oxidations of phenols: Enantioselective synthesis of (+)- and (-)-dehydrodiconiferyl alcohol

Article abstract of DOI:10.1055/s-1999-2595

Stereoselective bimolecular radical coupling reactions of phenylpropenoid phenols are described. Oppolzer's camphor sultam 1 and Evans's 2-oxazolidinone 2a-d derivatives of ferulic acid were prepared and oxidized to give dimeric benzofuran neolignan structures 11 in 40-50% overall yields. The chiral phenols were oxidized either enzymatically with hydrogen peroxide and horseradish peroxidase (HRP) or by silver oxide. The observed enantioselectivity after reductive cleavage of chiral auxiliaries gave the neolignan dehydrodiconiferyl alcohol 12 in 18-84% e.e.

Full text of DOI:10.1055/s-1999-2595

LETTER
333
Asymmetric Biomimetic Oxidations of Phenols: Enantioselective
Synthesis of (+)- and (-)-Dehydrodiconiferyl Alcohol
Petteri Rummakko,a,b* Gösta Brunow,a Marco Orlandi,c and Bruno Rindonec
a Department of Chemistry, P.O.Box 55 FIN-00014 University of Helsinki, Finland
b Current address, Department of Pharmacy, P.O.Box 5B, FIN-00014 University of Helsinki, Finland
Fax (+358) 9 708 59556, E-mail: Petteri.Rummakko@Helsinki.fi
c Department of Environmental Sciences, University of Milan, Via Emanuell 15, 20126 Milan, Italy
Received 13 November 1998
chemical yields of 40-50% and enantiomeric excesses of
12 up to 84%. Two chiral auxiliaries, Oppolzer’s (+)-
2,10-camphor sultam 1 and Evans’s 2-oxazolidinones 2a-
d, were used to induce asymmetry in phenol oxidations.
Abstract: Stereoselective bimolecular radical coupling reactions of
phenylpropenoid phenols are described. Oppolzer’s camphor sul-
tam 1 and Evans’s 2-oxazolidinone 2a-d derivatives of ferulic acid
were prepared and oxidized to give dimeric benzofuran neolignan
structures 11 in 40-50% overall yields. The chiral phenols were ox-
idized either enzymatically with hydrogen peroxide and horseradish
peroxidase (HRP) or by silver oxide. The observed enantioselectiv-
ity after reductive cleavage of chiral auxiliaries gave the neolignan
dehydrodiconiferyl alcohol 12 in 18-84% e.e.
Key words: asymmetric synthesis, radical, phenol coupling, chiral
auxiliary
We have recently reported a stereocontrolled enzymatic
oxidative coupling of phenylpropenoid phenols.1 In that
work ferulic acid 3 covalently bound to a homochiral
amino acid by an amide bond was oxidized with horse-
radish peroxidase (HRP) in 65% enantioselectivity. Also,
Charlton et al. have reported that chiral sinapate esters can
be coupled with FeCl3 to aryltetralin lignan structures
with moderate stereoselectivity.2 The effects of cyclodex-
trins on the coupling of coniferyl alcohol was studied by
Hirai et al.3 but the observed e.e. values for oxidations
performed in b-cyclodextrin were less than 10%.
The N-acyloxazolidinone derivatives 5a-d of THP
protected9 ferulic acid 4 were prepared by using the mixed
anhydride N-lithiated oxazolidinone procedure (Scheme
1, Route A).10,11 The deprotection of THP-ethers 5a-d was
performed conveniently by using ion-exchange resin
(Amberlyst® IR-120) in methanol. The corresponding
camphor sultam derivative 9 was prepared from protected
ferulic acid chloride 7 under standard conditions (Route
B).12 Deprotection of the acetylated hydroxyl group of 8,
to obtain phenol 9, was performed according to the meth-
od reported previously.14
The biosynthetic pathway to (+)-pinoresinol has been elu-
cidated quite recently. A protein has been isolated from
Forsythia suspensa and found to be responsible for the
formation of enantiomerically pure (+)-pinoresinol from
E-coniferyl alcohol.4 The importance of free radical reac-
tions in organic synthesis has been increasing5 and meth-
ods to control stereochemistry in free radical reactions
have been found in recent years.6 Our interest has been to
extend the scope of asymmetric radical reactions into ox-
idative coupling reactions of phenols.
The problems of controlling regio- and stereoselectivity in
phenol oxidations have limited the use of these reactions
in organic synthesis. By careful selection of the reaction
conditions the regioselectivity can be improved.7 Lignan
total syntheses are often known to involve multistep pro-
cedures with low overall yields.8 Biomimetic oxidative
coupling reactions of cinnamyl alcohols and acids provide
a straightforward and cheap method for the preparation of
various lignan and neolignan structures. We performed
the oxidative coupling reaction of phenols using chiral
auxiliaries to produce benzofuran neolignans 11 with
Route A, a: i) MeOH, H+, ii) CH2Cl2, DHP, PPTS, 92% b: i) KOH/
EtOH, H3O+, 90%, ii)Pivaloyl chloride, Et3N, THF, -78 oC and BuLi,
o
2-oxazolidinone 2a-d, THF, -78 C, 70-80% c: MeOH, Amberlyst®
IR-120, 40 oC, 95%. Route B, d: i) Pyridine, Acetic anhydride, 90%,
ii) SOCl2, reflux e: Camphor sultam 1, NaH, Toluene, ca.70% f:
MeONa, MeOH, 95%.
Scheme 1
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334
P. Rummakko et al.
LETTER
Oxazolidinones 6a-d and camphor sultam 913 were oxi- alkylation reactions11 and to the results of Sibi et al. in
dized either enzymatically with HRP/H2O2 or chemically radical allylation reactions with the same type of auxilia-
with silver oxide (Scheme 2).7,15 Enzymatic oxidations ries.18
were performed in aqueous buffer containing acetone or
Attempts to use Lewis acid additives in phenol oxidations
to restrict the rotational freedom of N-acyl oxazolidinones
via chelative interactions failed. Addition of MgBr2 or Zn-
triflate to the oxidation with Ag2O of 6a prevented the re-
action completely. It seems that the use of Lewis acids to
control conformational rotamers via chelative interactions
is not possible in phenol oxidations.
dioxane as the co-solvent.16 Silver oxide oxidations were
performed in dry dichloromethane. After the dimerization
step the camphor sultam auxiliaries were removed by re-
duction with LiAlH4/THF12 and the oxazolidinones were
removed by reduction with LiBH4/THF.17 Table 1 gives
the results for the oxidations of chiral phenols 6a-d and 9.
In conclusion, these preliminary results demonstrate that
chiral auxiliaries provide significant levels of diastereo-
selection in bimolecular coupling reactions of phenoxyl
radicals and it is expected that this methodology could be
extended to various lignan structures thus providing a new
approach to the synthesis of valuable lignans.
Acknowledgement
Financial support for this work was provided by the Technology
Development Centre of Finland (TEKES) and The Academy of Fin-
land. We thank also the Italian Ministry for Scientific Research for
financial support.
Key a: Oxidation with Ag2O/CH2Cl2 in Argon or enzymatically with
HRP/H2O2, acetone or dioxane/buffer pH 3.5 b: Reduction with
LiAlH4 /THF, -20 oC or LiBH4/ THF, -20 oC, (1 equiv. H2O).
Scheme 2
References and notes
(1) Bolzacchini, E.; Brunow, G.; Meinardi, S.; Orlandi, M.;
Rindone, B.; Rummakko, P.; Setälä, H. Tetrahedron Lett.
1998, 39, 3291.
(2) Bogucki, D.E.; Charlton, J.L. Can. J. Chem. 1997, 75, 1783.
(3) Hirai, N.; Okamoto, M.; Udagawa, H.; Yamamuro, M.; Kato,
M.; Koshimizu, K. Biosci. Biotech. Biochem. 1994, 58, 1679.
(4) Davin, L.B.; Wang, H.B.; Crowell, A.L.; Bedgar, D.L.;
Martin, D.M.; Sarkanen, S.; Lewis, N.G. Science 1997, 275,
362.
(5) Giese, B. “Radicals in Organic Synthesis: Formation of Car-
bon-Carbon Bonds” Pergamon Press: Oxford (1986);
Jasperse, C.P.; Curran, D.P.; Fevig, T. Chem.Rev. 1991, 91,
1237.
(6) Reviews on stereochemistry in free radical reactions: Curran,
D.P.; Porter, N.A.; Giese, B. “ Stereochemistry of Radical Re-
actions; Concepts, Guidelines and Synthetic Applications,”
VCH: Weinheim, 1996; Kim, B.H.; Curran, D.P. Tetrahedron
1993, 49, 293; Smadja, W. Synlett 1994, 1; Porter, N.A.;
Giese, B.; Curran, D.P. Acc. Chem. Res. 1991, 24, 296.
(7) Chioccara, F.; Poli, S.; Rindone, B.; Pilati, T.; Brunow, G.;
Pietikäinen, P.; Setälä, H. Acta Chem. Scand. 1993, 47, 610.
(8) Ward, R.S. Nat. Prod. Rep. 1997, 14, 43.
(9) Miyashita, N.; Yoshikoshi, A.; Grieco, P.A. J. Org. Chem.
1977, 42, 3772.
(10) Ager, D.J.; Allen, D.R.; Schaad, D.R. Synthesis 1996, 1283.
(11) Evans, D.A.; Chapman, K.T.; Bisaha, J. J. Am. Chem. Soc.
The results show that among the auxiliaries used in oxida-
tions the camphor sultam 1 gives better results that the
corresponding oxazolidinones 2a-d. The reason for this is
probably the better rotational control of the camphor sul-
tam compared to 2-oxazolidinones.6 The temperature and
solvent had only minor effects on the observed stereo-
selectivity. Among the oxazolidinone auxiliaries the ster-
ically smaller phenyl oxazolidinone gave considerably
higher selectivities (e.e. 62%) compared to the corre-
sponding benzyl oxazolidinone (e.e. 21%). This observa-
tion is opposite to the results of Evans in Diels-Alder and
1988, 110, 1238.
(12) Oppolzer, W.; Chapuis, C.; Bernardinelli, G. Helv. Chim. Acta
1984, 67, 1397.
(13) Experimental data for phenol 6c and 9. Compound 6c 1H
NMR (200 MHz, CDCl3) d: 3.93 (s, 1H), 4.31 (dd, J=4.0, 8.8
Hz, 1H), 4.74 (t, J=8.8 Hz, 1H), 5.57 (dd, J=4.0, 8.8 Hz, 1H),
5.97 (s, 1H), 6.90 (d, J=8.1 Hz, 1H), 7.10 (s, 1H), 7.12 (d,
J=7.8 Hz, 1H), 7.32-7.39 (m, 5H), 7.71 (d, J=15.8 Hz, 1H),
7.80 (d, J=15.8 Hz, 1H). 13C NMR (75 MHz, CDCl3) d: 56.0,
57.9, 69.9, 109.5, 114.0, 114.6, 124.1, 125.9, 127.1, 128.6,
129.1, 139.1, 146.7, 146.9, 148.4, 153.8, 164.8. HREIMS cal-
Synlett 1999, No. 3, 333–335 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Enantioselective Synthesis of (+)- and (-)-Dehydrodiconiferyl Alcohol
335
culated for C19H17O5N 339.1107, found 339.1098. MS m/z
ml) was added to the reaction mixture. The acetone was remo-
ved by evaporation and the products were extracted with ethyl
acetate (2 x 20 ml). The combined organic layers were dried
with Na2SO4 and evaporated. The remainig yellowish foam
(350 mg) was partially purified (250 mg) with column chro-
matography (silica gel, ethyl acetate / toluene). The purificati-
on gave (110 mg) benzofuran diastereoisomers in 4/1 ratio.
The major diastereoisomer white powder 11c (R* = 2c). 1H
NMR (200 MHz, CDCl3) d: 3.81 (s, 3H), 3.90 (s, 3H), 4.30
(dd, J=3.5, 8.8 Hz, 2H), 4.74 (t, J=8.8 Hz, 1H), 4.85 (t, J=8.8
Hz, 1H), 5.50 (dd, J=3.5, 8.6 Hz, 1H), 5.56 (dd, J=3.6, 8.6 Hz,
1H), 5.69 (s, 1H), 5.83 (d, J=7.6 Hz, 1H), 6.00 (d, J=7.6 Hz,
1H), 6.71 (d, J=8.0 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 6.85 (s,
1H), 7.07 (s, 2H), 7.32-7.43 (m, 10H), 7.70 (d, J=15.6 Hz,
1H), 7.77 (d J=15.6 Hz, 1H). 13C NMR (75 MHz, CDCl3) d:
54.0, 55.1, 55.6, 57.7, 57.9, 69.5, 69.9, 88,2, 108.4, 112.1,
113.9, 114.1, 117.9, 119.3, 125.5, 126.3, 128.4, 128.5, 128.8,
130.1, 138.1, 145.7, 146.2, 150.4, 153.1, 153.5, 164.3, 170.1.
FAB MS m/z 677 (M+ +1).
(%) = 339 [M]+ (100), 177 (90), 145 (20), [a]D25 6c (c = 0.91,
CHCl3) = -32.1. Compound 9 1H NMR (200 MHz, CDCl3) d:
0.99 (s, 3H), 1.21 (s, 3H), 1.25-1.45 (m, 3H), 1.85-1.96 (m,
3H), 2.15-2.20 (m, 2H), 3.51 (d, J=3.8 Hz, 2H), 3.92 (s, 3H),
3.99 (dd, J=5.5, 7.0 Hz, 1H), 5.89 (s 1H), 6.88-7.19 (m, 4H),
7.73 (d, J=15.3 Hz, 1H). 13CNMR (75 MHz, CDCl3) d: 20.2,
21.1, 26.8, 33.1, 38.8, 45.0, 48.1, 48.7, 53.5, 56.3, 65.6, 110,1,
115.0, 124.2, 127.2, 146.1, 147.0, 148.7, 164.8. HREIMS of
8 (the acetate of 9) calculated for C22H27O6NS 433.1559,
found 433.1573. MS m/z (%) = 433 [M]+ (10), 391 (65), 177
(100). [a]D23 9 (c = 0.43, CHCl3) = +63.1.
(14) Boiadjiev, S.E.; Lightner, D.A. Tetrahedron: Asymmetry
1996, 7, 2825.
(15) Quideau, S.; Ralph, J. Holzforschung 1994, 48, 12.
(16) Typical experimental procedure for the enzymatic phenol
coupling. A solution of the phenol 6c (1.03 mmol) in acetone
(14 ml) and the 0.02 M phosphate/citric acid buffer (4 ml, pH
3.5) was cooled to 0 oC. Horseradish peroxidase (0.93 ml, 900
U/ml, 837 U) in water and 0.86 M H2O2 (0.60 ml, 0.52 mmol)
were alternately added to the reaction vessel in small portions
during 15 min. After addition the reaction mixture turned
cloudy and slightly yellow color appeared. The reaction was
stirred at 0 oC and after 4 hours saturated NaCl-solution (20
(17) Penning, T.D.; Djuric, S.W.; Haack, R.A.; Kalish, V.J.; Mi-
yashiro, J.M.; Rowell, B.W.; Yu, S.S. Synth. Commun. 1990,
20, 307.
(18) Sibi, M.P.; Ji, J. Angew. Chem. Int. Ed. Engl. 1996, 35, 190.
Synlett 1999, No. 3, 333–335 ISSN 0936-5214 © Thieme Stuttgart · New York