TRIP-Catalyzed Asymmetric Synthesis of (+)-Yatein, (-)-α-Conidendrin, (+)-Isostegane, and (+)-Neoisostegane

Article abstract of DOI:10.1021/acs.joc.9b00065

The asymmetric allylation under the assistance of catalytic amounts of 3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate (TRIP) allows the concise construction of the lignan scaffold from simple aldehydes and allylic bromides with full control of the two formed stereocenters. This young methodology has been employed to synthesize four naturally and pharmaceutically active lignans. Members of the dibenzylbutyrolactone, the tetraline, and the dibenzocyclooctadiene classes have been synthesized in 40-47% overall yield along four-step synthetic routes.

Full text of DOI:10.1021/acs.joc.9b00065

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Note
TRIP-Catalyzed Asymmetric Synthesis of (+)-Yatein,
(-)-#-Conidendrin, (+)-Iso- and (+)-Neoisostegane.
Peter Hartmann, Mattia Lazzarotto, Lorenz Steiner, Emmanuel
Cigan, Silvan Poschenrieder, Peter Sagmeister, and Michael Fuchs
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00065 • Publication Date (Web): 28 Mar 2019
Downloaded from http://pubs.acs.org on March 28, 2019
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Page 1 of 8
The Journal of Organic Chemistry
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TRIP-Catalyzed Asymmetric Synthesis of (+)-Yatein, (-)--Conidendrin,
(+)-Iso- and (+)-Neoisostegane.
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Peter Hartmann, Mattia Lazzarotto, Lorenz Steiner, Emmanuel Cigan, Silvan Poschenrieder, Peter
Sagmeister, Michael Fuchs*.
University of Graz, Institute of Chemistry, Bioorganic and Organic Chemistry, Heinrichstrasse 28/II, 8010 Graz, Austria,
Europe.
Supporting Information Placeholder
MeO
MeO
O
O
O
O
MeO
O
O
O
OH
MeO
MeO
MeO
MeO
(R)-TRIP,
Zn0, NH4Cl
OMe
isostegane
neoisostegane
O
O
+
O
R
R
MeO
HO
O
O
O
O
Br
O
O
O
92-98% ee
>95:<5 d.r.
4 natural products
4-5 steps lls
40-47% overall yield
highly stereoselective
OMe
OMe
MeO
yatein
OH
-conidendrin
OMe
ABSTRACT: The asymmetric allylation under the assistance of catalytic amounts of 3,3′-Bis(2,4,6-triisopropylphenyl)-1,1′-
binaphthyl-2,2′-diyl hydrogenphosphate (TRIP) allows the concise construction of the lignan scaffold from simple aldehydes and
allylic bromides with full control of the two formed stereocenters. This young methodology has been employed to synthesize four
naturally and pharmaceutically active lignans. Members of the dibenzylbutyrolactone-, the tetraline- and the dibenzocyclooctadiene-
class have been synthesized in 40-47% overall yield along four steps synthetic routes.
Plant metabolites have been a key foundation of traditional folk
medicine for thousands of years and deliver today a plethora of
lead structures for medicinal chemistry.1 One of these classes of
metabolites is summarized as lignans, which describe a group
consisting of dimeric phenylpropanes, linked at the C8 carbon
(see Figure 1).2
The bioactivity of this compound class has reached an
impressive range: antiviral,3-5 anticancer,5-7 cancer prevention,8,
9
7, 10
anti-inflammatory,7 antimicrobial,7 antioxidant,6,
immunosuppressive,7 hepatoprotective11 and osteoporosis
prevention12 have been reported or suggested. This
pharmalogical attractiveness has triggered plenty of synthetic
endeavours. Nevertheless, a short concise asymmetric synthesis
of the substructure has remained troublesome until recently. We
have been able to show that chiral phosphoric acids (CPAs),
especially 3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-
2,2′-diyl hydrogenphosphate (TRIP, 1), provide catalytic
stereoinduction on the allylation of benzaldehydes (see Scheme
1).13 We were able to demonstrate the applicability of the
developed methodology on the natural product (-)-
hydroxymatairesinol (9, see Figure 2). In order to further
expand the portfolio of lignan natural products available within
short synthetic procedures we envisaged the other classes of
compounds herein.
R
R
O
Ar
Ar
Ar
Ar
Ar
O
O
Ar
O
O
O
Lignan
subcore
dibenzyl-
butyrolactones
Furo-
furans
R
R
Dibenzo
cyclooctadienes
O
O
O
O
Ar
Ar
Aryltetralins
Figure 1. Lignan subcore and examples for the diversity of lignan
natural products.
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Page 2 of 8
iPr
The third class of lignan natural products are
iPr
O
1
2
3
4
5
6
7
8
dibenzylbutyrolactones. We were able to show the application
of the developed allylation methodology to the synthesis of (-)-
hydroxymatairesinol (9) previously.13 Nevertheless, we were
also able to obtain (-)-yatein (10), another lignan natural
product of this subclass, on the route to isostegane (5).
Br
iPr
O
P
O
iPr
2
O
O
O
OH
(R)-TRIP (10 mol-%)
OH
Zn, NH4Cl
O
O
toluene/iPr2O, rt, 16 h
R
R
iPr
iPr
up to 99% ee
up to >99:<1 d.r.
1
(R)-TRIP (
)
The retrosynthetic strategy is outlined in Scheme 2. Isostegane
(5) and neoisostegane (6) can be accessed via an ironIII mediated
aryl-aryl coupling.35 Yatein (10) is simply obtained from the
corresponding hydroxyl-dibenzylbutyrolactone precursor via
hydrogenative dehydroxylation under acidic conditions.31 (-)--
Conidendrin (8) can be easily prepared via a Friedel-Crafts
alkylation under acidic conditions from the corresponding
hydroxy-dibenzylbutyrolactone.31, 36 The latter key intermediate
can be obtained via RhI-catalyzed 1,4-addition of the
arylboronate37, 38 and the previously reported TRIP-catalyzed
asymmetric allylation.13
Scheme 1. Asymmetric allylation of aldehydes yielding the
butyrolactone core of lignans.
9
The first targets demonstrate the cyclooctadienes isostegane14-
21 and neoisostegane22-24 (5 and 6, see Figure 2). Stegane natural
products show a high potential as pharmacophores, as they
provide strong inhibition of the tubulin assembly,25 a process of
high importance in the treatment of cancer. Isostegane (5) is a
synthetic congener of the lignan steganacine, whereas
neoisostegane (6) was isolated directly from the plant. Both
10
11
12
13
14
15
16
17
18
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22
23
24
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60
compounds were found in the extracts of steganotaenia
araliacea26,
but interestingly possess the opposite axial
27
iron mediated
cyclization
chirality.26, 28 Most probably the substitution in C5 position (see
Figure 2, structures 3 and 4) defines the different alignment for
the cyclization step in case of steganacine’s biosynthesis.
R
R
O
O
O
O
Dibenzocyclooctadienes:
MeO
R'
R'
R
10
(+)-yatein (
)
5
iso-stegane ( ) and
O
O
6
neoisostegane (
R
)
O
O
X
hydrogenative
dehydroxylation
MeO
5
5
5
FC-
alkylation
O
O
O
MeO
MeO
OH
O
O
O
MeO
MeO
MeO
MeO
O
O
O
O
OMe
MeO
MeO
R'
prepared
within
this study
5
6
)
isostegane (
)
neoisostegane (
R'
3
8
)
X = H ... stegane (
X = OH ... steganol (
)
(-)--conidendrin (
9
(-)-hydroxymatairesinol (
)
4
)
RhI cat. 1,4-
addition
Aryltetralins:
Dibenzylbutyrolactones:
OH
OH
4
R
R
O
OH
O
O
MeO
O
O
O
+
O
O
O
TRIP cat.
asymmetric
allylation
HO
O
O
prepared
in previous
study
Br
MeO
OMe
OMe
OMe
OH
Scheme 2. General retrosythetic analysis and natural products en
route.
7
podophyllotoxin ( , usual
9
(-)-hydroxymatairesinol (
)
aryltetralin structure)
O
O
MeO
O
As the first synthetic target we picked isostegane (5, see Scheme
3 for forward synthesis). By our previous study of this reaction13
we knew that the (R)-configured catalyst 1 should yield the right
enantiomer. The asymmetric allylation of piperonal proved
more difficult than expected and required further reaction
optimization. Under the previously published standard
conditions13 we observed diminished values for the
enantiomeric excess (82%) and only moderate yields for 12 (see
Table 1, entry 1). This fact may be attributed to the cyclic ether
moiety, which can – due to its freely available lone pairs – act
as a Lewis base itself and lower the activation energy of the
uncatalyzed background reaction. The same phenomenon was
observed for furyl substituents in our previous study.13 In order
to prevent this unwanted side reaction, we studied the reaction
again with regard to the reaction medium, as we observed a high
influence of the latter. Dilution of the reaction and higher
concentration of the allylating reagent increased the
enantiomeric excess again into the nineties, whereas the yield
was only improved slightly (see Table 1, entry 2). Therefore we
omitted the polar component of the reaction medium – namely
diisopropylether – and increased the concentration again. This
gave a significant boost to the conversion with only a slightly
O
4
O
HO
O
prepared
within
this study
prepared
within
this study
OMe
OMe
MeO
OMe
OH
(-)--conidendrin (
10
(-)-yatein (
)
8
)
Figure 2. Representatives of lignan natural products and target
molecules of this study.
Another lignan natural product is (-)--conidendrin (8).29-31
This compound has been a template for studies onto the C4
configuration of pharmacophores like podophyllotoxin (7) and
sikkimotoxin.32 Especially interesting is the different
orientation of the lactone carbonyl moiety in the aryltetralin
structure when compared to other representatives of the natural
product subclass (see structures 7 and 8 in Figure 2) and this
compound class has been the most prominent studied as
podophyllotoxin (7) is the precursor to frequently used
chemotherapeutics.33, 34
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The Journal of Organic Chemistry
worse stereoutcome (see Table 1, entry 3). Having the solvent
see Table 1). However, the dimethoxy motif showed
significantly more background reaction, probably by chelating
a Zn2+ ion in between the two lewis basic lone pairs of the
methoxy groups. The only way to prevent this increased
background activity was to add higher amounts of catalyst (40
mol-%), which lead to similar results as for piperonal. Neither
lower temperatures nor less polar reaction medium (e.g.
cyclohexane cosolvent) allowed to reduce the high catalyst
loading. The Michael acceptor 16 was then subjected to the
same synthetic route as outlined for the preparation of
isostegane (5): 1,4-Addition of the trimethoxy aromat in the
presence of RhI, dehydroxylation via palladium on charcoal and
hydrogen under acidic conditions and the same iron mediated
cyclization step of the dibenzocyclooctadiene provided 6 in
43% overall yield over four steps. The last step of the sequence
proved to be less selective in terms of diastereoselectivity [d.r.
of 4.2:1 in favor of the desired natural product 6 (see Scheme
4); the other diastereoisomer is referred to as compound 24 (see
experimental section)]. This may be attributed to the ortho-
substituent of the trimethoxy substituted aromatic fragment,
which may show more steric interaction with the benzylic CH2-
group23,35 or exhibit electronic repulsion between the methoxy
oxygen lone pair(s) and the lactone carbonyl group and hamper
the proper alignment for the cyclization. Nonetheless, the
diastereomers could be separated via preparative HPLC and full
characterization of both compounds was achieved. The optical
rotation values for 6 and 24 show significant differences {6:
[α]D20 = +105.2 (c = 1.68, CHCl3), lit.: [α]D20 = +107.7 (c = 0.51,
1
2
3
4
5
6
7
8
system set, the next step was to further improve the
enantiomeric excess, which was achieved by diluting the
reaction again (see Table 1, entries 4 and 5). In order to supply
an appropriate amount of starting material the reaction was
scaled up and the values from the analytical scale experiments
could be reproduced almost perfectly (see Table 1, entry 6).
Table 1. Reaction optimization – asymmetric allylation of
piperonal (11).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Conc.
[mM]
54
14
54
Conv.a)
[%]
52
68
94
eeb)
[%]
82
91
89
Entry
Solvent
1c)
2
3
Toluene /iPr2O
Toluene/ iPr2O
Toluene
4
Toluene
34
85
92
5
Toluene
Toluene
23
23
82
94
92
6d)
81d)
Reaction conditions: piperonal (11, 27 µmol), 2 (3.4 eq.), Zn0
(6.3 eq.), NH4Cl (9.0 eq.), (R)-TRIP (1, 20 mol-%), for solvent
and substrate concentration see table; a) the conversion was
determined via HPLC-UV at 215 nm; b) determined via HPLC-
UV on a chiral stationary phase; c) standard reaction conditions
from initial study: 2 (1.5 eq.);13 d) preparative scale on 0.27
mmol substrate; isolated yield is reported for this entry.
Having product 12 in hand, the second benzylic group was
easily attached using a rhodium(I) catalyzed 1,4-addition to the
exocyclic double bond yielding dibenzylbutyrolactone (14).37, 38
Simple hydrogenation under acidic conditions removed the
benzylic hydroxyl function cleanly and provided
(-)-yatein (10) in 3 steps from piperonal (11) with an overall
CHCl3)24 and 24: [α]D = -119.6 (c = 0.26, CHCl3)}. The
20
stereochemical assignment was obtained via the coupling
constants in the 1H-NMR spectra, which show doublets for the
5-proton and the 8-proton is case of the iso-configuration,
whereas the natural configuration of stegane yields a doublet of
a doublet, as the coupling towards protons 6 and 7 becomes >0
Hz (for proton numbering see Scheme 4, structure 6).27 The
20
22
yield of 51% {[α]D = -16.06 (c = 1.1, CHCl3), lit.: [α]D = -
30.0 (c = 0.15, CHCl3)39}. Treating this natural product with
iron(III) perchlorate in the presence of trifluoroacetic acid gave
1
absence of the H,1H-NOESY cross peak in the spectra of
20
20
isostegane {5, [α]D = +165.4 (c = 0.41, CHCl3), lit.: [α]D
=
compounds 6 and 24 of the two adjacent protons of the lactone
ring confirms the trans substition of the five-membered ring.
+154.0 (c = 0.7, CHCl3)19} and the dibenzocyclooctadiene core
of the natural product class in 92% yield and 47% overall yield
via a four steps synthetic route. This compound differs from
stegane only by the axial chirality of the biaryl system and can
be interconverted into the latter by simply heating it up (200°C,
39% yield, 61% recovered isostegane).19
(R)-TRIP
O
OH
OH
[RhIcodCl]2
,
(40 mol-%),
Zn0, NH4Cl
MeO
MeO
MeO
MeO
MeO
O 4/1, MeO
70°C, 3 h, 72%
17, Et3
N
O
O
O
+
toluene, 4°C,
16 h, >99%
dioxane/H2
15
2
O
O
O
16
, 95% ee
>95:<5 d.r.
Br
MeO
MeO
18
,
>95:<5
d.r.
(R)-TRIP
OMe
O
OH
OH
[RhIcodCl]2
13, Et3
,
(20 mol-%),
Zn0, NH4Cl
MeO
Pd/C, H2 (1 atm.), HClO4
,
O
O
O
O
N
O
O
EtOH, 16 h, 79%
O
O
O
+
MeO
MeO
HO
OH
5
6
toluene, rt,
16 h, 81%
dioxane/H2O 4/1,
70°C, 3 h, 87%
B
MeO
MeO
11
Fe(ClO4) ,
3
2
14
,
O
O
O
OMe
12
, 92% ee
>95:<5 d.r.
Br
O
O
O
>95:<5
d.r.
CH2Cl2/TFA 10/1,
rt, 21 h, 76%
7
OMe
8
OMe
O
MeO
MeO
MeO
17
OMe
OMe
OMe
19
MeO
O
Pd/C, H2 (1 atm.), HClO4
EtOH, 16 h, 72%
,
6
(+)-neoisostegane (
)
O
OMe
O
O
B
O
Fe(ClO4) ,
3
O
O
MeO
MeO
CH2Cl2/TFA 10/1,
rt, 1 h, 92%
Scheme 4. Forward synthesis of (+)-neoisostegane (6).
O
MeO
OMe
10
(-)-yatein (
)
O
O
13
OMe
Next, we aimed at the aryltetraline motif. For this matter, (-)-
hydroxymatairesinol (9) was prepared as previously described13
and simlply treated with trifluoroacetic acid (see Scheme 5).
MeO
(+)-isostegane (
OMe
MeO
5
)
OMe
20
Scheme 3. Forward synthesis of (-)-yatein (10) and (+)-isostegane
(5).
The reaction provided cleanly (-)--conidendrin {8, [α]D = -
35.8 (c = 0.35, acetone), lit.: [α]D20 = -51.6 (c = 2.1, acetone)31}
in 76% yield. This refers to 40% overall yield over the four step
synthetic route (see Scheme 5).
The same reaction sequence was tested with aldehyde 15 in
order to obtain the corresponding precursors for the
neoisostegane natural product (6). The allylation sequence was
tested under the same reaction conditions as for piperonal (11,
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(R)-TRIP
O
OH
OH
Polarimeter 341 or an Anton Paar MCP5100 unit. Compounds
[RhIcodCl]2
22, Et3
,
(20 mol-%),
Zn0, NH4Cl
MeO
BnO
MeO
BnO
MeO
BnO
N
2 and 9 were prepared as previously described.13
1
2
3
4
5
6
7
8
O
O
O
O
+
toluene/iPr2O,
4°C, 16 h, 71%
dioxane/H2O 4/1,
70°C, 3 h, 87%
20
23
,
O
O
21
, 97% ee
>95:<5 d.r.
Br
>95:<5
d.r.
(R)-4-[(S)-benzo[d][1,3]dioxol-5-yl(hydroxy)methyl]-3-
methylenedihydrofuran-2(3H)-one (12). (R)-TRIP (40 mg,
0.053 mmol, 20 mol-%), zinc dust (< 10 µm, 110 mg, 1.7
mmol), ammonium chloride (130 mg, 2.4 mmol) and piperonal
(11, 40 mg, 0.27 mmol) were combined in a round bottom flask.
Toluene (8 mL) was added, followed by allylic bromide 2 (71.7
mg, 0.41 mmol) and the mixture was stirred for 16 h at room
temperature. The reaction was quenched by the addition of
NH4Clsat., aq. solution (10 mL). The mixture was extracted with
EtOAc (3 x 15 mL), the combined organic phase was dried over
Na2SO4, filtered and concentrated. The obtained crude product
was purified via flash chromatography (SiO2, hexanes/EtOAc
2
OMe
OH
OH
OMe
Pd/C, H2 (1 atm.),
EtOAc, 16 h, 86%
O
O
B
OH
HO
MeO
(-)--conidendrin (
MeO
HO
CH2Cl2/TFA 8/1,
rt, 24 h, 76%
O
O
O
OMe
22
OH
O
8
)
9
OMe
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OH
(-)-hydroxymatairesinol (
9
)
Scheme 5. Forward synthesis of (-)--conidendrin (8).
In conclusion we have shown the applicability of our recently
developed asymmetric allylation protocol via the preparation of
four different lignan natural products. We were able to achieve
high yielding and concise protocols (40 – 47% overall yield
over four steps) for three additional subclasses of lignan natural
products – namely dibenzylbutyrolactones (represented by
hydroxymatairesinol and yatein), aryltetralins (represented by
-conidendrin) and dibenzocyclooctadienes (represented
neoisostegane). After reoptimization the allylation key step
provided the desired precursors in high yields (71 – >99%) and
excellent stereoselectivities (92 – 98% ee, d.r. = >95:<5),
although on the expense of high catalyst loadings, in order to
suppress the racemic background reaction.
3/1 to 2/1) to give the title compound 12 as a white solid (54
20
mg, 0.22 mmol, 81%). Mp: 107-109 °C (from CDCl3); [α]D
=
1
+8.9 (c = 0.91, CHCl3); H-NMR (300 MHz, CDCl3): 6.84 (s,
1H), 6.78 (s, 2H), 6.35 (d, J = 2.1, 1H), 5.97 (s, 2H), 5.86 (d, J
= 2.1, 1H), 4.59 (d, J = 8.0, 1H), 4.15 (dd, J1 = 9.6, J2 = 8.3,
1H), 4.01 (dd, J1 = 9.6, J2 = 4.5, 1H), 3.39-3.30 (m, 1H), 2.25
(br s, 1H); 13C{1H}-NMR (75 MHz, CDCl3): 170.8, 148.3,
147.9, 135.2, 134.8, 125.6, 120.4, 108.4, 106.8, 101.4, 75.6,
67.6, 45.6; IR (film) ῦ = 3408, 1733, 1488, 1443, 1396, 1379,
1248, 1144, 1039, 1005, 958, 930, 821; HRMS(ESI): m/z: calc.
+
for C13H13O5 : 249.0758 [M+H]+, found: 249.0756; HPLC
analysis on a chiral stationary phase: Daicel Chiralpak IA (4.6
x 250 mm, 5 µm particle size), n-heptane/2-propanol 75/25, 1.0
mL/min, 30 °C, UV 230 nm, tret(enantiomer 1) = 8.0 min,
tret(enantiomer 2) = 10.2 min}: tret(major isomer) = 10.2 min, ee
= 92%.
EXPERIMENTAL SECTION
General.
(3R,4R)-4-[(S)-benzo[d][1,3]dioxol-5-yl(hydroxy)methyl]-3-
All chemicals were purchased from Sigma Aldrich or Acros
Organics and were used as received unless otherwise noted. All
solvents were purchased from Roth. All moisture sensitive
reactions were operated using standard Schlenk techniques with
dry argon. Analytical thin layer chromatography (TLC) was
carried out on Merck TLC silica gel aluminum sheets (silica gel
60, F254, 20 x 20 cm) and spots were visualized by UV light (λ
= 254 nm) and by staining with cerium ammonium molybdate
solution [50 g (NH4)6Mo7O24 were dissolved in 400 mL H2O
and 50 mL conc. H2SO4 was added followed by 2.0 g Ce(SO4)2]
or KMnO4 solution (1 g KMnO4 and 2 g Na2CO3 were dissolved
in 100 mL H2O) and developed by heating with a heat gun.
Column chromatography was performed on silica gel 60 from
Merck with particle sizes 40-63 µm. A 30- to 100-fold excess
of silica gel was used with respect to the mass of dry crude
product, depending on the separation problem. NMR spectra
were recorded on a Bruker NMR unit at 300 (1H) and 75 (13C)
MHz, shifts are given in ppm and coupling constants (J) are
given in Hz. Deuterated solvents for nuclear resonance
spectroscopy were purchased from Roth. IR-spectra were
recorded neat on a Bruker Alpha-P (ATR) instrument. Melting
points were determined on a Gallenkamp MPD350.BM2.5
apparatus with an integrated microscopical support. They were
measured in open capillary tubes with a mercury-in-glass
thermometer and were not corrected. High resolution mass
spectra were recorded on an Agilent 6230 TOF LC/MS using
ESI (positive mode, capillary voltage 1.6 kV) or APCI (negative
mode, 5.0 kV) methods. Chiral HPLC analysis was performed
on a Shimadzu HPLC system with n-heptane/2-PrOH as eluent.
Optical rotation values were measured on a Perkin Elmer
(3,4,5-trimethoxybenzyl)dihydrofuran-2(3H)-one
(14).
[Rh(cod)Cl]2 (3 mg, 0.007 mmol), the boronic acid pinacol ester
13 (97 mg, 0.33 mmol) and 12 (54 mg, 0.22 mmol) were
dissolved in dioxane (600 µL). Water (150 µL) and Et3N (30
µL, 22 mg, 0.22 mmol) were added and the mixture was stirred
at 70°C for 3 h. The obtained orange solution was diluted with
EtOAc (10 mL), washed with NaHCO3 sat., aq. solution and the
aqueous solution was reextracted with EtOAc (2 x 10 mL). The
combined organic phase was washed with brine, dried over
Na2SO4, filtered and concentrated under reduced pressure. The
crude product was purified via flash chromatography (SiO2,
toluene/EtOAc 3/1) to give the desired compound 14 as a
colorless oil (80 mg, 0.19 mmol, 87%). [α]D20 = -10.6 (c = 1.45,
CHCl3); 1H-NMR (300 MHz, CDCl3): 6.74-6.66 (m, 3H), 6.35
(s, 2H), 5.95 (dd, J1 = 3.8, J2 = 1.2, 2H), 4.62 (d, J = 6.5, 1H),
3.94 (d, J = 7.6, 2H), 3.80 (s, 9H), 3.04-2.85 (m, 3H), 2.60 (p, J
= 7.2, 1H), 2.36 (br s, 1H); 13C{1H}-NMR (75 MHz, CDCl3):
179.1, 153.0, 148.1, 147.5, 136.6, 135.5, 133.3, 119.2, 108.2,
106.6, 106.1, 101.3, 75.2, 68.4, 60.8, 56.1, 45.0, 43.6, 35.5; IR
(film) ῦ = 3487 (br), 2939, 2839, 1757, 1591, 1505, 1488, 1459,
1443, 1422, 1384, 1348, 1322, 1237, 1185, 1123, 1033, 1005,
+
909, 813, 782, 726; HRMS(ESI): m/z: calc. for C22H24O8NH4 :
434.1809 [M+NH4]+, found: 434.1809.
(-)-Yatein (10). Comound 14 (68 mg, 0.16 mmol) was
dissolved in EtOH (5.5 mL). Pd/C (10 wt-%, 20.4 mg, 2.0 mg
Pd, 0.019 mmol, 0.07 eq.) and HClO4 (70 wt-%, 15 µL) were
added and the reaction mixture was placed under an atmosphere
of hydrogen and stirred for 16 h. The mixture was passed
through a pad of celite, the pad was washed with EtOAc (20
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The Journal of Organic Chemistry
mL) and the combined filtrate was washed with NaHCO3 sat., aq.
2.34 (br s, 1H); 13C{1H}-NMR (75 MHz, CDCl3): 170.8, 149.4,
149.3, 135.3, 133.4, 125.5, 119.1, 111.1, 109.4, 75.7, 67.7, 56.1,
45.7; IR (film) ῦ = 3249 (br), 1760, 1751, 1516, 1507, 1461,
1260, 1237, 1143, 1123, 1022, 1003, 988, 950, 912, 856, 818,
725, 649; HPLC analysis on a chiral stationary phase: Daicel
Chiralpak IE (4.6 x 250 mm, 5 µm particle size), n-heptane/2-
propanol 70/30, 0.9 mL/min, 30 °C, UV 215 nm, tret(enantiomer
1) = 11.8 min, tret(enantiomer 2) = 13.2 min}: tret(major isomer)
1
2
3
4
5
6
7
8
solution (10 mL). The phases were separated and the aqueous
phase was reextracted with EtOAc (2 x 20 mL) and the
combined organic phase was dried over Na2SO4, filtered and
concentrated. The obtained crude product was purified via flash
chromatography (SiO2, hexanes/EtOAc 1/1) to give product 10
as yellow oil (46 mg, 0.11 mmol, 72%). [α]D20 = -16.06 (c = 1.1,
CHCl3), lit.: [α]D22 = -30.0 (c = 0.15, CHCl3);39 1H-NMR (300
MHz, CDCl3): δ 6.72 – 6.66 (m, 1H), 6.50 – 6.43 (m, 2H), 6.35
(s, 2H), 5.93 (dd, J1 = 2.9, J2 = 1.4 Hz, 2H), 4.17 (dd, J1 = 9.2,
J2 = 7.1 Hz, 1H), 3.90-3.85 (m, 1H), 3.83 (s, 6H), 3.82 (s, 3H),
2.90 (dd, J1 = 5.8, J2 = 3.2 Hz, 2H), 2.66 – 2.41 (m, 4H);
13C{1H}-NMR (75 MHz, CDCl3): 178.7, 153.4, 148.1, 146.5,
137.0, 133.5, 131.7, 121.7, 108.9, 108.4, 106.3, 101.2, 71.3,
61.0, 56.2, 46.6, 41.2, 38.5, 35.4; IR (film) ῦ = 2937, 2840,
1764, 1590, 1504, 1489, 1459, 1444, 1422, 1345, 1320, 1239,
1186, 1124, 1035, 1011, 909, 810, 726; HRMS(ESI): m/z: calc.
=
13.3 min, ee = 95%; HRMS(ESI): m/z: calc. for
+
C14H16O5NH4 : 282.1336 [M+NH4]+, found: 282.1338.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(3R,4R)-4-[(S)-(3,4-dimethoxyphenyl)(hydroxy)methyl]-3-
(2,3,4-trimethoxybenzyl)dihydrofuran-2(3H)-one
(18).
[Rh(cod)Cl]2 (3 mg, 0.007 mmol), the (2,3,4-
trimethoxyphenyl)boronic acid (17, 64 mg, 0.30 mmol), Et3N
(28 µL, 20 mg, 0.2 mmol) and lactone 16 (52 mg, 0.20 mmol)
were dissolved in dioxane/water 4/1 (600 µL) in a 10 mL
Biotage vial. The vial was capped and crimped and placed in a
preheated oil bath (55°C oil bath temperature) and stirred for 20
h. The reaction mixture was cooled to room temperature,
quenched in NaHCO3 aq.,sat. solution (10 mL) and the obtained
slurry was extracted with EtOAc (3 x 10 mL). The combined
organic phase was dried over Na2SO4, filtered and concentrated
under reduced pressure. The crude product was purified via
flash chromatography (SiO2, toluene/EtOAc 1/1) to give the
desired compound 18 as a yellow oil (62 mg, 0.14 mmol, 72%).
[α]D20 = -23.8 (c = 0.41, CHCl3); 1H-NMR (300 MHz, CDCl3):
6.88 (d, J = 8.6 Hz, 1H), 6.82 – 6.70 (m, 3H), 6.60 (d, J = 8.6
Hz, 1H), 4.50 (d, J = 8.0 Hz, 1H), 3.92 (s, 3H), 3.89 (s, 3H),
3.87 – 3.82 (m, 2H), 3.85 (s, 3H), 3.85 (s, 3H), 3.84 (s, 3H),
3.10 (qd, J1 = 13.9, J2 = 5.7 Hz, 2H), 2.93 (dt, J1 = 7.9, J2 = 5.7
Hz, 1H), 2.55 (p, J = 7.8 Hz, 1H); 13C{1H}-NMR (75 MHz,
CDCl3): 178.9, 153.0, 151.5, 149.4, 149.1, 142.1, 134.4, 125.6,
123.3, 118.3, 111.3, 109.3, 108.1, 76.4, 68.6, 61.3, 61.0, 56.1,
56.0, 45.9, 44.5, 29.5; IR (film) ῦ = 3496 (br), 3008, 2937, 2837,
1754, 1603, 1514, 1494, 1465, 1417, 1257, 1234, 1184, 1153,
1139, 1095, 1023, 808, 748; HRMS(ESI): m/z: calc. for
+
for C22H25O7 : 401.1595 [M+H]+, found: 401.1594.
(+)-Isostegane (5). (-)-Yatein (10, 24.0 mg, 0.06 mmol) was
dissolved in CH2Cl2 (1.0 mL). Fe(ClO4)3 (50.0 mg, 0.14 mmol,
2.4 eq.) was added, followed by trifluoroacetic acid (100 µL,
149 mg, 1.3 mmol, 22 eq.). The reaction mixture was stirred at
room temperature for 1 h. The reaction mixture was quenched
by the addition of NaHCO3 sat., aq. solution and the mixture was
extracted with EtOAc (3 x 10 mL). The combined organic phase
was dried over Na2SO4, filtered and concentrated under reduced
pressure. The crude product was purified via flash
chromatography (SiO2, hexanes/EtOAc 1/1) to give 5 as a
yellow oil (21.8 mg, 0.055 mmol, 92% yield). [α]D20 = +165.4
(c = 0.41, CHCl3), lit.: [α]D20 = +154.0 (c = 0.7, CHCl3);19 1H-
NMR (300 MHz, CDCl3): 6.70 (s, 1H), 6.62 (s, 1H), 6.62 (s,
1H), 6.00 (d, J = 1.4, 1H), 5.97 (d, J = 1.4 Hz, 2H), 4.37 (dd, J1
= 8.4, J2 = 6.3 Hz, 1H), 3.89 (s, 3H), 3.88 (s, 4H), 3.77 (dd, J1
= 11.1, J2 = 8.7 Hz, 1H), 3.57 (s, 3H), 3.12 (d, J = 13.3 Hz, 1H),
2.64 (d, J = 13.1 Hz, 1H), 2.39 (dd, J1 = 13.1, J2 = 9.3 Hz, 1H),
2.29 (dd, J1 = 13.3, J2 = 9.1 Hz, 1H), 2.14 – 2.04 (m, 1H);
13C{1H}-NMR (75 MHz, CDCl3): 176.7, 153.5, 152.0, 147.8,
146.1, 141.0, 136.2, 132.5, 128.5, 126.6, 111.9, 108.9, 107.6,
101.4, 70.2, 61.1, 61.0, 56.2, 50.2, 47.2, 34.3, 32.5; IR (film) ῦ
= 2922, 2852, 1772, 1595, 1482, 1454, 1403, 1339, 1223, 1142,
1119, 1102, 1081, 1034, 994, 921; HRMS(ESI): m/z: calc. for
+
C23H28O8NH4 : 450.2122 [M+NH4]+, found: 450.2130.
(3R,4R)-4-(3,4-dimethoxybenzyl)-3-(3,4,5-
trimethoxybenzyl)dihydrofuran-2(3H)-one (19). Comound
18 (60 mg, 0.14 mmol) was dissolved in MeOH (3 mL). Pd/C
(10 wt-%, 30.0 mg, 3.0mg Pd, 0.03 mmol, 0.2 eq.) and HClO4
(70 wt-%, 30 µL) were added and the reaction mixture was
placed under an atmosphere of hydrogen and stirred for 16 h.
The mixture was passed through a pad of celite, the pad was
washed with CH2Cl2 (10 mL) and the combined filtrate was
+
C22H23O7 : 399.1438 [M+H]+, found: 399.1437.
(R)-4-[(S)-(3,4-dimethoxyphenyl)(hydroxy)methyl]-3-
methylenedihydrofuran-2(3H)-one (16). (R)-TRIP (84 mg,
0.112 mmol, 40 mol-%), zinc dust (< 10 µm, 112 mg, 1.7
mmol), ammonium chloride (128 mg, 2.4 mmol) and 3,4-
dimethoxybenzaldehyde (15, 46 mg, 0.28 mmol) were
combined in a round bottom flask. Toluene (11.4 mL) was
added, followed by allylic bromide 2 (168 mg, 0.95 mmol) and
the mixture was stirred for 16 h at 4°C. The reaction was
quenched by the addition of NH4Clsat., aq. solution (10 mL). The
mixture was extracted with EtOAc (3 x 15 mL), the combined
organic phase was dried over Na2SO4, filtered and concentrated.
The obtained crude product was purified via flash
chromatography (SiO2, toluene/EtOAc 3/2) to give the title
compound 16 as a white solid (74 mg, 0.28 mmol, >99%). Mp:
70-74 °C (from CDCl3); [α]D20 = +14.4 (c = 1.7, acetone); 1H-
NMR (300 MHz, CDCl3): δ 6.88 – 6.85 (m, 3H), 6.36 (d, J =
1.9, 1H), 5.85 (dd, J1 = 2.1, J2 = 0.7 Hz, 1H), 4.62 (d, J = 8.0
Hz, 1H), 4.15 (dd, J1 = 9.6, J2 = 8.3 Hz, 1H), 4.02 (dd, J1 = 9.6,
J2 = 4.4 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.43 – 3.33 (m, 1H),
washed
with
NaHCO3, aq.,sat. solution (10 mL). The aqueous phase was
reextracted with CH2Cl2 (2 x 10 mL) and the combined organic
phase was dried over Na2SO4, filtered and concentrated. The
obtained crude product was purified via flash chromatography
(SiO2, cyclohexane/EtOAc 2/1) to give product 19 as yellow oil
(46 mg, 0.11 mmol, 79%). [α]D20 = -44.0 (c = 2.3, CHCl3), lit.:
[α]D22 = -48.6 (c = 1.23, CHCl3);24 1H-NMR (300 MHz, CDCl3):
6.88 (d, J = 8.5 Hz, 1H), 6.72 (d, J = 8.7 Hz, 1H), 6.60 (d, J =
8.5 Hz, 1H), 6.58 – 6.49 (m, 2H), 4.10 (dd, J1 = 9.1, J2 = 7.2 Hz,
1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.89 – 3.80 (m, 1H), 3.83 (s,
3H), 3.83 (s, 3H), 3.82 (s, 3H), 3.15 (dd, J1 = 13.8, J2 = 5.0 Hz,
1H), 2.83 (dd, J1 = 13.8, J2 = 7.6 Hz, 1H), 2.73 – 2.44 (m, 3H),
2.34 (dd, J1 = 13.2, J2 = 9.1 Hz, 1H); 13C{1H}-NMR (75 MHz,
CDCl3): 178.9, 153.0, 152.2, 149.1, 147.9, 142.3, 131.1, 125.1,
123.9, 120.6, 111.9, 111.4, 107.5, 71.5, 61.0, 60.9, 56.1, 56.0,
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The Journal of Organic Chemistry
55.9, 45.8, 42.1, 38.3, 29.6; IR (film) ῦ = 3000, 2936, 2836,
Page 6 of 8
0.076 mmol, 76%). Mp: 224-226 °C (from acetone), lit.: 222-
224°C;31 [α]D20 = -35.8 (c = 0.35, acetone), lit.: [α]D20 = -51.6 (c
= 2.1, acetone);31 1H-NMR (300 MHz, methanol-d4): 6.78-6.75
(m, 2H), 6.69 – 6.63 (m, 2H), 6.26 (s, 1H), 4.22 – 4.03 (m, 2H),
3.90 (d, J = 10.6 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.12 (dd,
J1 = 15.5, J2 = 4.8 Hz, 1H), 3.00 – 2.83 (m, 1H), 2.74-2.52 (m,
2H); 13C{1H}-NMR (75 MHz, methanol-d4): 180.0, 149.4,
147.9, 146.7, 145.9, 135.8, 133.3, 127.5, 122.4, 117.0, 116.3,
113.3, 112.7, 73.4, 56.4, 50.7, 43.0, 30.2; IR (film) ῦ = 3402
(br), 2956, 2929, 2522, 1757, 1613, 1598, 1583, 1509, 1468,
1440, 1426, 1365, 1351, 1323, 1242, 1196, 1153, 1109, 1086,
1027, 995, 927, 913, 890, 873, 779, 748, 733; HRMS(ESI): m/z:
1
2
3
4
5
6
7
8
1765, 1601, 1514, 1494, 1464, 1417, 1381, 1261, 1235, 1198,
1154, 1095, 1065, 1012, 804, 749; HRMS(ESI): m/z: calc. for
+
C23H28O7NH4 : 434.2173 [M+NH4]+, found: 434.2173.
(+)-Neoisostegane (6). Compound 19 (36 mg, 86 µmol) was
dissolved in CH2Cl2 (1.4 mL). Fe(ClO4)3.7H2O (73 mg, 210
µmol) and trifluoroacetic acid (140 µL) were added and the
reaction mixture was stirred at room temperature for 21 h. The
reaction was quenched by the addition of NaHCO3 aq.,sat. solution
(5 mL) and the mixture was extracted with EtOAc (3 x 10 mL).
The combined organic phase was dried over Na2SO4, filtered
and concentrated. The obtained crude product was purified via
flash chromatography (SiO2, cyclohexane/EtOAc 3/2) to give a
mixture of compound 6 and diastereoisomer 24 (32 mg, 77
µmol, 90%, d.r. = 4.2 : 1 in favour of compound 6). This
mixture was further purified via preparative HPLC
[Phenomenex LUNA AXIATM pack (5 µm, C18(2), 100 Å, 250
x 21.2 mm), 30 mL/min flow, isocratic eluent: H2O/MeCN
60/40] to give neoisostegane (6, 27 mg, 65 µmol, 76%) as a pale
yellow oil (from CHCl3) and compound 24 (4.2 mg, 10 µmol,
12%) as a pale yellow oil (from CHCl3).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
calc. for C20H21O6 : 357.1333 [M+H]+, found: 357.1332.
+
ASSOCIATED CONTENT
Supporting Information
1
For H- and 13C-NMR data and HPLC chromatograms see the
electronic supporting information.
The Supporting Information is available free of charge on the ACS
Publications website.
(+)-Neoisostegane (6): [α]D20 = +105.2 (c = 1.68, CHCl3), lit.:
NMR and HPLC data (PDF)
20
[α]D = +107.7 (c = 0.51, CHCl3);24 1H-NMR (300 MHz,
AUTHOR INFORMATION
Corresponding Author
* Michael Fuchs, Institute of Chemistry, Bioorganic and Organic
Chemistry, Heinrichstrasse 28/II, 8010 Graz, Austria, Europe;
mail to: michael.fuchs@uni-graz.at.
CDCl3): 6.71 (s, 1H), 6.68 (s, 1H), 6.51 (s, 1H), 4.38 (dd, J1 =
8.4, J2 = 6.7 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 6H), 3.87 (s, 3H),
3.85 (s, 3H), 3.77 (dd, J1 = 11.3, J2 = 8.4 Hz, 1H), 3.67 (d, J =
13.0 Hz, 1H), 2.66 (d, J = 13.1 Hz, 1H), 2.41 (dd, J1 = 13.2, J2
= 9.9 Hz, 1H), 2.28-2.15 (m, 1H), 2.02 (dd, J1 = 13.0, J2 = 9.1
Hz, 1H), 1.91 (dd, J1 = 13.1, J2 = 9.2 Hz, 1H); 13C{1H}-NMR
(75 MHz, CDCl3): 176.4, 151.6, 150.7, 149.0, 147.5, 142.1,
136.3, 132.6, 131.0, 126.8, 114.1, 112.3, 109.8, 70.1, 61.2, 60.9,
56.24, 56.22, 56.20, 49.9, 46.9, 34.4, 24.2; IR (film) ῦ = 3013,
2936, 2847, 1774, 1603, 1570, 1517, 1490, 1464, 1445, 1398,
1341, 1326, 1280, 1253, 1224, 1209, 1172, 1117, 1098, 1081,
1066, 1035, 994, 958, 938, 914, 845, 701, 747; HRMS(ESI):
Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the
manuscript.
ACKNOWLEDGMENT
+
m/z: calc. for C23H26O7NH4 : 432.2017 [M+NH4]+, found:
M. Fuchs and M. Lazzarotto are grateful for an FWF grant (P
31276-B21). Philipp Neu and Thomas Eichmann are highly
acknowledged for the HRMS measurements and Bernd Werner and
Prof. Klaus Zangger are thanked for assistance with the recording
of the NMR spectra. W. Kroutil is highly acknowledged for
financial and scientific support throughout the whole work.
432.2023
20
Compound 24: [α]D = -119.6 (c = 0.26,
O
MeO
1
O
CHCl3); H-NMR (300 MHz, CDCl3): 6.74
(s, 1H), 6.59 (s, 1H), 6.44 (s, 1H), 4.32 (dd,
J1 = 8.5, J2 = 7.5 Hz, 1H), 3.92 (s, 3H), 3.91
(s, 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.84 (s,
24
MeO
OMe
MeO
OMe
REFERENCES
proposed structure
3H), 3.76 (dd, J1 = 11.0, J2 = 8.5 Hz, 1H),
(1)
Newman, D. J. Natural Products as Leads to Potential
3.38 (dd, J1 = 15.9, J2 = 7.7 Hz, 1H), 2.96 (dd, J1 = 14.6, J2 =
7.9 Hz, 1H), 2.73 (dd, J1 = 15.9, J2 = 7.9 Hz, 1H), 2.62 – 2.47
(m, 1H), 2.43 – 2.33 (m, 2H); 13C{1H}-NMR (75 MHz, CDCl3):
178.8, 152.0, 151.6, 148.3, 147.7, 141.7, 137.1, 134.4, 128.6,
123.8, 114.0, 113.1, 110.1, 70.5, 61.2, 61.0, 56.28, 56.24, 56.17,
42.2, 40.8, 33.3, 29.9, 25.1; IR (film) ῦ = 2933, 2851, 1768,
1603, 1569, 1517, 1488, 1463, 1448, 1420, 1399, 1346, 1318,
1261, 1247, 1213, 1169, 1144, 1116, 1095, 1071, 1049, 1010,
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J. Med. Chem. 2008, 51, 2589-2599.
(2)
Peng, Y., Lignans, Lignins, and Resveratrols. In From
Biosynthesis to Total Synthesis: Strategies and Tactics for
Natural Products, Zografos, A. L., Ed. John Wiley & Sons,
Inc.: New Jersey, 2016; pp 331-379.
(3)
Charlton, J. L. Antiviral Activity of Lignans. J. Nat.
Prod. 1998, 61, 1447-1451.
+
991, 955, 935, 911; HRMS(ESI): m/z: calc. for C23H26O7NH4 :
(4)
Cos, P.; Maes, L.; Vlietinck, A.; Pieters, L. Plant-
432.2017 [M+NH4]+, found: 432.2022.
Derived Leading Compounds for Chemotherapy of Human
Immunodefiency Virus (HIV) Infection – An Update (1998ꢀ–
ꢀ2007). Planta Med. 2008, 74, 1323-1337.
(-)--Conidendrin (8). Hydroxymatairesinol (9, 37 mg, 0.1
mmol) was dissolved in CH2Cl2 (200 µL). Trifluoroacetic acid
(25 µL, 37 mg, 0.33, 3.3 eq.) was added and the reaction
mixture was stirred for 24 h at room temperature. The obtained
solution was directly applied to flash chromatography (silica
gel, hexanes/EtOAc 1/2) to give (-)--conidendrin (8, 27 mg,
(5)
Morteza, Y.; Mozafar, S.; Mehrdad, B.; Elisabeth, M.;
Mercedis, B.; M., C. R.; Javier, P. Podophyllotoxin: Current
approaches to its biotechnological production and future
challenges. Eng. Life Sci. 2010, 10, 281-292.
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The Journal of Organic Chemistry
Pan, J.-Y.; Chen, S.-L.; Yang, M.-H.; Wu, J.; Bisphosphine-Rhodium(I) Complex. Heterocycles 1990, 30,
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1
2
3
4
5
6
7
8
Sinkkonen, J.; Zou, K. An update on lignans: natural products
and synthesis. Nat. Prod. Rep. 2009, 26, 1251-1292.
363-366.
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