Synthesis of sterically hindered chiral 1,4-diols from different lignan-based backbones

Article abstract of DOI:10.1055/s-0033-1340084

Methods for synthetic modifications of the natural dibenzylbutyrolactone lignan hydroxymatairesinol into chiral 1,4-diols with different lignan-derived backbones have been developed. A stepwise procedure, involving alkylation and oxidation, was shown to b

Full text of DOI:10.1055/s-0033-1340084

LETTER
▌2423
lSetyternthesis of Sterically Hindered Chiral 1,4-Diols from Different Lignan-Based
Backbones
Synthesis of Sterically Hindered Chiral 1,4-Diols
Yury Brusentsev,a Mikko M. Hänninen,b Patrik Eklund*a
a
Laboratory of Organic Chemistry, Åbo Akademi University, Biskopsgatan 8, 20500 Åbo (Turku), Finland
E-mail: paeklund@abo.fi
b
Department of Chemistry, University of Jyväskylä, P.O. Box 35, 40014, Jyväskylä, Finland
Received: 06.09.2013; Accepted after revision: 14.10.2013
Abstract: Methods for synthetic modifications of the natural diben-
zylbutyrolactone lignan hydroxymatairesinol into chiral 1,4-diols
with different lignan-derived backbones have been developed. A
stepwise procedure, involving alkylation and oxidation, was shown
to be successful and several highly substituted 1,4-diols were pre-
pared. Some substituted butyrolactones resisted alkylation and led
to the formation unusually stable hemiketals (butyrolactols). The
formation of stable hemiketals was investigated in detail, showing
that different backbone structures influence the formation and reac-
tivity of the hemiketals.
Key words: hydroxymatairesinol, chiral 1,4-diols, TADDOL, lig-
nans, burtyrolactol
Yury Brusentsev (right) obtained his master degree in chemistry
from Moscow State University in 2003. He worked as a researcher in
R&D (drug development) for pharmaceutical industry until 2009 and
moved back to academia and is currently carrying out his PhD in the
group of Patrik Eklund at Åbo Akademi University. His research in-
terests are in advanced organic synthesis, organometallic chemistry,
Utilizing wood-derived compounds as high-value chemi-
cals has become increasingly important due to the devel-
opment of biorefinery processes. Norway spruce (Picea
abies) is highly abundant and one of the most economical-
ly important coniferous species in Europe. The knotwood
of Norway spruce has been shown to be rich in polyphe-
nolic compounds with up to 20% of its dry weight consist-
ing of the lignan hydroxymatairesinol.1 The synthetic
modification of hydroxymatairesinol to high-value com-
pounds has been of interest to us for several years.
catalysis, and organocatalysis.
Patrik Eklund (left) obtained his master degree in chemistry from
Åbo Akademi University in 2000. Following this he worked for Hor-
mos Medical Ltd. for a short period. In 2002 he started his PhD stud-
ies under the supervision of Prof. Rainer Sjöholm at Åbo Akademi
University. He completed his PhD in 2005 in the field of synthetic
modification of the natural products and continued as a research fel-
low and lecturer until 2006 when he was appointed as a senior lecturer
in organic chemistry at the Laboratory of Organic Chemistry, Åbo
Akademi University. In 2009 he was appointed as an adjunct profes-
sor in organic synthesis and natural product chemistry. His current re-
search is focused on natural product synthesis, semisynthesis of
anticancer agents, drug discovery, and structural determination and
chemical modification of noncellulosic natural polysaccharides.
We have recently investigated the possibility of trans-
forming hydroxymatairesinol into sterically hindered li-
gands (similar to TADDOL). Several chiral 1,4-diol
structures based on the aryltetralin skeleton of dimethyl-
conidendrin (1, Scheme 1) have been synthesized and
their potential application as ligands in asymmetric catal-
ysis investigated.2 When converting an intermediate sub-
stituted butyrolactone 3, by addition of Grignard or alkyl
lithium reagents, stable hemiketals 4 were predominantly
formed. Only the methyl-substituted lactone formed the
diol 5 (Scheme 1). It was shown that one reason for this
problem was the steric bulk of the lignan backbone, but
even in case of the less bulky methyl groups the main
product was still the hemiketal. Surprisingly, the forma-
tion of hemiketals for TADDOL-like structures has only
rarely been reported in the literature. However, recent pa-
pers on TADDOL derivatives have addressed similar
problems.3,4
To overcome this problem and to study the stability of the
hemiketals, we decided to investigate the reactivity of oth-
er lignan-derived backbones, with the hypothesis that
more flexible and accessible backbones would react to
give the target 1,4-diols. For this purpose, three new lig-
nan backbones were selected: dimethylmatairesinol (6a),
a fully flexible structure, the macrocycle 6c with a slightly
more fixed conformation, and a cyclooctadiene structure
6b with a more rigid structure (Scheme 2).
The use of hydroxymatairesinol as a starting material gave
access to the enantiopure butyrolactone with the 8R,8R′
configuration, the configuration of these stereocentres be-
ing preserved during the synthetic modifications.
Hydroxymatairesinol was first converted into matairesin-
ol by catalytic hydrogenolysis on Pd/C (Scheme 2).5
Compound 6a was then prepared in almost quantitative
yield from matairesinol by methylation with methyl io-
SYNLETT 2013, 24, 2423–2426
Advanced online publication: 21.10.2013
DOI: 10.1055/s-0033-1340084; Art ID: ST-2013-D0863-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

2424
Y. Brusentsev et al.
LETTER
detailed experimental information see Supporting Infor-
mation.
O
H
H
MeO
MeO
O
These results are in good agreement with the observations
by Budragchaa et al.3 In a similar synthesis of TADDOL-
like structures, stable substituted hemiketals were formed
and the introduction of the fourth substituent took up to 48
hours. In the case of lactones 8a and 8c, formation of a
close to 50:50 mixture of the hemiketal (one diastereo-
mer) and the tetramethyl diol was observed in one hour,
and by addition of more methylmagnesium bromide very
slow conversion of the hemiketal into tetramethyl diol
(several days) was observed. A more detailed study of the
reaction mixture (by NMR) indicated that predominatly
one of the hemiketals reacted with a moderate rate, where-
as the other reacted slowly.
R = Ph, Me, 2-naphthyl
MeO
OMe
dimethylconidendrin (1)
RLi
85–95%
R
R
H
H
H
R
R
O
MeO
MeO
MeO
OH
OH
MeO
PCC
H
O
62–88%
O
H
MeO
MeO
MeO
8'R
O
OMe
OMe
8R
3
HO
2
HO
H
RMgBr or RLi
43–57%
37%
R
H
MeO
H
H
R
MeO
MeO
MeO
MeO
Pd/C, H2
OH
hydroxymatairesinol
OH
OH
O
OH
H
R
O
H
H
MeO
HO
MeO
MeO
MeO
O
OMe
OMe
O
H
H
(i)
MeO
5
4
O
Scheme 1 Transformation of dimethylconidendrin (1) into chiral
95%
MeO
diols2
MeO
MeO
6a
OH
dide. Compound 6b was prepared from 6a by intramolec-
ular oxidative coupling mediated by vanadium
oxyfluoride in good yield.6 For preparation of the macro-
cyclic compound 6c, the phenolic groups of matairesinol
were first allylated to give 10 and then cyclized by ring-
closing metathesis to give 11, followed by hydrogenation
of the double bond (for details see Supporting Informa-
tion).
matairesinol
(iii) 95%
MeO
(ii)
74%
MeO
O
H
H
MeO
MeO
O
O
H
H
O
O
O
The lactones 6a–c were then methylated with methylmag-
nesium bromide to afford compounds 7a–c in excellent
yields. The diols 7a–c were further oxidized with pyridin-
ium chlorochromate (PCC) in good to excellent yields to
the lactones 8a–c (Scheme 3).
MeO
10
6b
MeO
MeO
(iv) 55%
MeO
O
O
When the substituted lactones 8a and 8c were reacted with
methylmagnesium bromide, a mixture of hemiketals (dia-
stereomers) was first formed, but with excess of methyl-
magnesium bromide the diols 9a and 9c were slowly
obtained (Scheme 4). In case of the lactone 8b, the mix-
ture of hemiketals (S)- and (R)-9b was stable and did not
undergo any further reactions regardless of the reaction
conditions. Experimental details for methylation of the
lactones 8a–c as well as some analytical data for com-
pounds 9a–c are presented in the references.7 For more
H
H
H
O
O
(v)
O
O
95%
O
O
H
MeO
MeO
6c
11
Scheme 2 Synthesis of different lactone backbones. Reagents and
conditions: (i) MeI (5 equiv), K2CO3, DMF, r.t. 3 h; (ii) VOF3 (3
equiv), TFA–CH2Cl2, –45 °C; (iii) allyl bromide (5 equiv), K2CO3,
DMF, r.t.; (iv) Grubbs I catalyst 5%, CH2Cl2, r.t.; (v) 5% Pd/C,
MeOH, r.t.
Synlett 2013, 24, 2423–2426
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Sterically Hindered Chiral 1,4-Diols
2425
of compound 4. The bond angles and the flexibility in the
butyrolactol ring clearly determined the reactivity of this
intermediate.
MeO
MeO
H
H
86%
O
MeO
MeO
The tetramethyl diol 9c was crystallized from benzene to
give single crystals suitable for X-ray diffraction. The re-
sulting molecular structure is shown in Figure 1. A strong
intramolecular hydrogen bond between the hydroxyl
groups [O···O′ distance 2.674(2) Å] induces a nonsym-
metrical structure in the solid state, and the parallel align-
ment of the aromatic rings is distorted by about 15°.
Furthermore, intermolecular hydrogen bonds link the di-
ols together forming molecular chains (Figure S1 in Sup-
porting Information). However, the NMR spectrum
shows the molecule to be completely symmetrical, which
indicates that the hydrogen bonding does not distort the
structure in solution.
O
O
H
O
8a
MeO
H
MeO
MeO
6a–c
H
H
(i)
77%
O
95–98%
O
H
(ii)
OH
OH
MeO
8b
H
7a–c
MeO
H
H
O
96%
O
O
O
MeO
8c
Scheme 3 Alkylation and oxidation of the different lactones 6a–c.
Reagents and conditions: (i) MeMgBr (3 equiv), THF, r.t.; (ii) PCC
(3 equiv), CH2Cl2, r.t.
Figure 1 X-ray structure of diol 9c. Thermal ellipsoids have been
drawn at 30% probability level and CH hydrogens are omitted for
clarity.
These observations, as well as the fact that compound 3
led to the formation of the unreactive butyrolactol 4 upon
alkylation, clearly showed that in a flexible backbone both
diastereomers of the hemiketals react further to furnish the
diols, but with considerable difference in reaction rate. In
a more rigid structure with a certain configuration and
conformation of the butyrolactol ring [compounds (S)-9b,
(R)-9b, and 4], further reaction to the diol was prevented.
For these stable hemiketals no equilibrium between the
ketone and the hemiketal was observed. Whatever the
configuration at the hemiketal carbon, the torsion angle
between OH and the oxygen in the butyrolactol ring were
of equal magnitude in (S)- and (R)-9b and similar to that
In conclusion, we have developed methods for diverse
synthetic modifications of the lignan skeleton of hydroxy-
matairesinol. The preparation of highly substituted 1,4-di-
ols was not straightforward due to formation of stable
hemiketals. This problem has recently been recognized
and has now been investigated in more detail by modifi-
cation of the backbone structure. According to our results,
the formation and further reactivity of highly substituted
butyrolactol (hemiketal) structures is only partially de-
pendent on the flexibility and bulkiness of the molecule.
MeO
H
MeO
MeO
MeO
OH
OH
MeMgBr
MeO
MeO
MeO
MeO
MeO
MeO
H
H
H
H
H
H
60%
MeMgBr
66%
MeMgBr
81%
O
O
O
9a
OH
OH
H
O
8a–c
MeO
MeO
MeO
H
H
O
(S)-9b
84:16
(R)-9b
OH
OH
O
MeO
9c
Scheme 4 Reaction of the dimethyl lactones 8a–c with methylmagnesium bromide. Reagents and conditions: MeMgBr (3–5 equiv), THF, r.t.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2423–2426

2426
Y. Brusentsev et al.
LETTER
give products 9a–c.
Analytical Data for Compounds 9a–c
A more important feature is the configuration and confor-
mation of the butyrolactol. The prepared sterically hin-
dered chiral diols could potentially be used as ligands in
transition-metal-mediated asymmetric catalysis.8,9 Fur-
ther transformation of 1,4-diols into chiral phosphine li-
gands is ongoing in our laboratory.
Compound 9a (reaction time 72 h, yield 265 mg, 60%): 1H
NMR (600 MHz, CDCl3): δ = 1.06 (s, 6 H), 1.23 (s, 6 H),
2.58 (dd, J = 7.1, 5.1 Hz, 2 H), 2.65 (dd, J = 14.9, 7.1 Hz, 2
H), 2.96 (dd, J = 14.9, 5.1 Hz, 2 H), 3.88 (s, 6 H), 3.90 (s, 6
H), 6.82 (d, J = 7.9 Hz, 2 H), 6.85 (d, J = 1.5 Hz, 2 H), 6.87
(dd, J = 7.9, 1.5 Hz, 2 H) ppm. 13C NMR (151 MHz, CDCl3):
δ = 26.3, 30.9, 33.9, 48.3, 55.9, 74.3, 111.2, 112.1, 120.5,
135.3, 147.2, 148.9 ppm.
Acknowledgment
Compound 9b (reaction time 20h, yield 350 mg, 0.81 mmol,
81%)
Dr. Annika Smeds for HRMS analyses and the Academy of Finland
for financial support (project #127137).
(S)-9b: 1H NMR (600 MHz, CDCl3): δ = 1.01 (s, 3 H), 1.44
(s, 3 H), 1.57 (s, 3 H), 1.77 (dd, J = 12.3, 10.0 Hz, 1 H), 2.07
(dd, J = 12.1, 10.2 Hz, 1 H), 2.13 (br s, 1 H), 2.20 (dd,
J = 13.0, 10.2 Hz, 1 H), 2.31 (dd, J = 13.6, 10.0 Hz, 1 H),
2.47 (d, J = 13.0 Hz, 1 H), 2.64 (d, J = 13.6 Hz, 1 H), 3.87
(s, 3 H), 3.89 (s, 3 H), 3.93 (s, 3 H), 3.96 (s, 3 H), 6.68 (s, 1
H), 6.71 (s, 1 H), 6.72 (s, 1 H), 6.74 (s, 1 H) ppm. 13C NMR
(151 MHz, CDCl3): δ = 22.9, 26.4, 28.9, 32.8, 33.3, 54.5,
55.2, 56.0, 56.06, 56.1, 56.2, 81.7, 102.9, 112.0, 112.1,
113.4, 113.6, 132.5, 132.6, 133.0, 133.2, 147.0, 147.1,
148.6, 148.7 ppm.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
Primary Data for this article are available online at
http://www.thieme-connect.com/ejournals/toc/synlett and can be
cited using the following DOI: 10.4125/pd0051th. mPiDrayramPtirDayra4t0.215p/d00P51hri
m
t.yarDaZataehnl101
C
hemyrsti
(R)-9b: 1H NMR (600 MHz, CDCl3): δ = 1.14 (s, 3 H), 1.28
(s, 3 H), 1.35 (s, 3 H), 1.69 (dd, J = 12.6, 10.6 Hz, 1 H), 2.08
(dd, J = 12.6, 10.0 Hz, 1 H), 2.13 (br. s., 1 H), 2.20 (dd,
J = 12.8, 10.0 Hz, 1 H), 2.22 (dd, J = 13.2, 10.6 Hz, 1 H),
2.42 (d, J = 13.2 Hz, 1 H), 2.73 (d, J = 12.8 Hz, 1 H), 3.88
(s, 3 H), 3.89 (s, 3 H), 3.94 (s, 3 H), 3.95 (s, 3 H), 6.66 (s, 1
H), 6.71 (s, 1 H), 6.74 (s, 1 H), 6.80 (s, 1 H) ppm. 13C NMR
(151 MHz, CDCl3): δ = 23.6, 24.4, 28.1, 32.9, 33.1, 55.9,
56.0, 56.1, 56.1, 56.1, 56.3, 80.5, 104.5, 111.9, 112.2, 113.3,
113.4, 132.3, 132.8, 132.9, 132.9, 147.0, 147.1, 148.6, 148.7
ppm.
References and Notes
(1) Holmbom, B.; Eckerman, C.; Eklund, P.; Hemming, J.;
Nisula, L.; Reunanen, M.; Sjöholm, R.; Sundberg, A.;
Willför, S. Phytochemistry Rev. 2003, 2, 331.
(2) Brusentsev, Y.; Sandberg, T.; Hotokka, M.; Sjöholm, R.;
Eklund, P. Tetrahedron Lett. 2013, 54, 1112.
(3) Budragchaa, T.; Rollerb, A.; Widhalm, M. Synthesis 2012,
44, 3238.
(4) Gratzer, K.; Waser, M. Synthesis 2012, 44, 3661.
(5) Markus, H.; Mäki-Arvela, P.; Kumar, N.; Kul’kova, N. V.;
Eklund, P.; Sjöholm, R.; Holmbom, B.; Salmi, T.; Murzin,
D. Y. Catal. Lett. 2005, 103, 125.
Compound 9c (reaction time 48 h, yield 310 mg, 0.66 mmol,
66%): 1H NMR (600 MHz, CDCl3): δ = 1.56 (s, 6 H), 1.65
(s, 6 H), 1.65–1.71 (m, 2 H), 1.87 (d, J = 10.6 Hz, 2 H), 2.06–
2.14 (m, 2 H), 2.62 (dd, J = 13.6, 10.6 Hz, 2 H), 2.76 (d,
J = 13.6 Hz, 2 H), 3.70 (br s, 2 H), 3.81 (s, 6 H), 4.17–4.23
(m, 2 H), 4.29–4.34 (m, 2 H), 6.26 (dd, J = 8.1, 1.9 Hz, 2 H),
(6) Cambie, R. C.; Clark, G. R.; Craw, P. A.; Rutledge, P. S.;
Woodgate, P. D. Aust. J. Chem. 1984, 1775.
(7) The dimethyl lactone 8a, 8b, or 8c (1 mmol) was dissolved
in THF (30 mL), the solution was cooled to 0 °C, and
MeMgBr (3 mL of 3 M solution in Et2O, 9 mmol) was added
dropwise during 30 min. The solution was allowed to warm
to r.t. and stirred for 20–72 h. Saturated NH4Cl (10 mL) and
H2O (10 mL) were added to the reaction mixture, and the
organic phase was separated. The aqueous phase was
extracted with CH2Cl2 (2 × 15 mL), and the combined
organic phases were dried over Na2SO4, filtered, and the
solvent evaporated. The residue was purified by column
chromatography using CHCl3–MeOH (70:1) as eluent, to
6.44 (d, J = 1.9 Hz, 2 H), 6.50 (d, J = 8.1 Hz, 2 H) ppm. 13
C
NMR (151 MHz, CDCl3): δ = 23.5, 30.9, 32.9, 37.7, 53.5,
55.9, 67.5, 74.4, 113.3, 113.5, 120.4, 134.5, 144.5, 148.1
ppm.
(8) Bee, C.; Han, S. B.; Hassan, A.; Iida, H.; Krische, M. J.
J. Am. Chem. Soc. 2008, 130, 2746.
(9) Perotti, J. P.; Cravero, R. M.; Luna, L. E.; Grau, R. J. A.;
Vaillard, S. E. ARKIVOC 2011, (xi), 92.
Synlett 2013, 24, 2423–2426
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