Bioinspired total synthesis of tetrahydrofuran lignans by tandem nucleophilic addition/redox isomerization/oxidative coupling and cycloetherification reactions as key steps

Article abstract of DOI:10.1039/c7ob02848b

A very short three-step approach to trans,trans,trans-2,5-diaryl-3,4-dimethyltetrahydrofuran lignans is reported. The carbon skeleton is assembled in a single step based on an unprecedented tandem reaction consisting of 1,2-addition of aryllithium reagents to α,β-unsaturated aldehydes, ruthenium-catalyzed redox isomerization of the resulting alkoxides to enolates and their dimerization triggered by single electron oxidation. The resulting 2,3-dialkyl-1,4-diketones form with moderate to good d/l-diastereoselectivity and are transformed to the target tetrahydrofuran lignans by reduction and diastereoselective cycloetherification.

Full text of DOI:10.1039/c7ob02848b

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DOI: 10.1039/C7OB02848B
Journal Name
ARTICLE
Bioinspired Total Synthesis of Tetrahydrofuran Lignans by Tandem
Nucleophilic Addition/Redox Isomerization/Oxidative Coupling
and Cycloetherification Reactions as Keysteps†
Received 00th January 20xx,
Accepted 00th January 20xx
Pratap R. Jagtap,a Ivana Císařová,b Ullrich Jahn*a
DOI: 10.1039/x0xx00000x
A very short three-step approach to trans,trans,trans-2,5-diaryl-3,4-dimethyltetrahydrofuran lignans is reported. The carbon
skeleton is assembled in a single step based on an unprecedented tandem reaction consisting of 1,2-addition of aryllithium
reagents to α,β-unsaturated aldehydes, ruthenium-catalyzed redox isomerization of the resulting alkoxides to enolates and
their dimerization triggered by single electron oxidation. The resulting 2,3-dialkyl-1,4-diketones form with moderate to good
d/l-diastereoselectivity and are transformed to the target tetrahydrofuran lignans by reduction and diastereoselective
cycloetherification.
www.rsc.org/
only way to gain access to larger amounts of the natural
products.
Introduction
Tetrahydrofuran lignans I-III are a large class of plant-based
natural products (Scheme 1).1 They form species-specific with
defined substitution patterns and stereochemistry at the
carbon atoms of the tetrahydrofuran rings. All THF lignans are
thought to result from the same achiral precursors coniferyl
alcohol IV (R = OH) or isoeugenol (R = H).2 They are subject to
OH
HO
OMe
OMe
OCH3
OH
R
R
HO
H
H
H
H
O
OH
OCH3
HO
H3CO
O
O
O
III
II Matairesinol
oxidative generation of radicals
V, which couple to quinone
HO
OMe
methides VII via presumed arrangement VI in the active site of
a dirigent protein. This sets the absolute stereochemistry at C3-
C4 and allows subsequent cyclization to pinoresinol VIII, which
I Lariciresinol
R
R
R
R
H
is enzymatically transformed to lignans of types
I and II. In
Dirigent
Protein
H
H
contrast, hydration of dimeric VII provides the diastereomeric
lignans of type III. It is noteworthy that tetrahydrofuran lignans
III with 3,4-cis- as well as 3,4-trans-dimethyl configuration were
isolated and the relative configuration of the 2,5-diaryl units
with respect to the 3,4-positions is variable. Even a THF lignan
with the sterically most demanding all-cis-configuration has
been very recently isolated,1f thus all relative and absolute
configurations at the tetrahydrofuran ring are found in the
natural products showing that the coupling stereochemistry of
radicals VI to quinone methides VII varies strongly, and also
suggesting strong constraints in the subsequent hydration step
from VII to tetrahydrofurans III. Since tetrahydrofuran lignans
display diverse and promising biological activities,1 but nature
typically provides only minute quantities, total synthesis is the
–e, –H+
OCH3
OCH3
OH
O
H3CO
OCH3
O
O
V
IV R = OH
R = H
VI
O
O
Ar
H
H
I
II
MeO
R = OH
Ar
O
R
H
VIII Pinoresinol
Ar = 4-HO-3-MeOC6H4
H
R
H2O
R = H
OMe
or
Ar
Ar
Ar
Ar
O
O
O
VII
3,4-trans-III
3,4-cis-III
Scheme 1 Major lignan classes containing the tetrahydrofuran ring and their
biosynthesis.
Common approaches to THF lignans of type III involve
alkylation of enolates
B by bromo ketones A, providing d,l-
diketones with good selectivity (Scheme 2).3 Their subsequent
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reductive cyclization gave predominately cis,trans,trans-2,5- phenolates IV during biosynthesis (cf. Scheme 1), VwieowuAlrdtictleriOgngliener
11
DOI: 10.1039/C7OB02848B
diaryl-3,4-dimethyltetrahydrofurans. Conjugate addition to
and cyclization furnished two diastereomers of tetrahydrofuran
C
dimerization to the lignan carbon framework in a single step.
We report here that such tandem organometallic-radical
lignans with cis,trans,cis configuration in a 7:1 ratio,4a as well as crossover reactions are indeed an efficient strategy to furnish
trans,trans,trans or cis,trans,trans configuration depending on 1,4-diketones with wide scope, good yield, and surprisingly
the configuration of the acyclic precursor, which had to be often good diastereoselectivity. They can be transformed in
separated from a 2.5:1 diastereomeric mixture before.4b
conjugate addition/radical cyclization approach of and
A
E
only two further steps to a number of tetrahydrofuran lignans
with reasonable diastereoselectivity.
D
provided tetrahydrofuran lignans with variable 2,5-trans- as
well as 2,5-cis-selectivity, but low 3,4-diastereoselectivity.5
Oxidative coupling reactions of cinnamic acid derivatives gave
low yields of 3,4-trans-tetrahydrofuran lignans with variable
2,5-diastereoselectivity.6 An azonia-Claisen rearrangement of
Results and discussion
An initial screening of new redox isomerization catalysts12
revealed that the catalyst system consisting of [Ru(p-
cymene)Cl2]2 and P(OMe)3 as a ligand9 is most efficient to
tertiary crotylamines
F and propionyl chloride G followed by
twofold addition provided trans,trans,trans-lignans with high
accomplish the critical isomerization of alkoxide
in quantitative yield and the shortest possible reaction time
(See the Electronic Supporting Information (ESI), Table S1).
3 to enolate 4
diastereoselectivity, but over eight steps.7
OTBS
NO2
+
O
Table 1 Tandem nucleophilic addition/redox isomerization/SET oxidation/dimerization
reactions (major d/l diastereomer shown).a
Br
Ar
CO2CH3
Ar
C
Ar
HO
Me2CuLi,
then
KHMDS, MeI
+
D
Ar
O
B
E
Ar
O
O
Ar-Br
tBuLi
+
A
CuCl2, then
Bu3SnH
Ar
R
Ar
Base
THF or
DME
–78 °C
H
R
2 mol%
[Ru(p-cymene)Cl2]2
2 mol% P(OMe)3
NR2
R
Cl
O
d/l-8
(R1O)n
(OR1)n
O
+
Ar-Li
AlCl3, then
2x ArLi
+
–78 to 84 °C, then
O
O
+
1
O
Ar
R
Ar
–
PF6
2
Fe+
G
III R1 = H, Me
, –78 °C
F
7
R
meso-8
OHC
This approach
Oxidative dimerization
2 = H
O
O
O O
ArLi
+
Ph
R
Ph
Ph
R
Ph
R
R
all in
DME
R2
1
2
R2
R2
R
EWG
EWG
8a R = H, THF, 62%, dr 6.5:1
8b R = Me, DME, 95%, dr 6:1
8c R = Et, DME, 69%, dr 7:1
8c R = Et, THF, 84%, dr 6:1
8d R = Pr, DME, 61%, dr 7:1
8e R = Ph,
8f R = 4-FC6H4,
8g R = 4-ClC6H4,
8h R = 4-MeOC6H4, 62%, dr 4:1
8i R = 2-MeOC6H4, 51%, dr 3:1
65%, dr 7:1
61%, dr 7:1
74%, dr 7:1
TMPO
EWG
EWG
5
Ru
cat.
LiO
LiO
O
ref. 9
Ar
Ar
3
4
Ar
H
H
O
R2
O
O
O
TMP = 2,2,6,6-tetramethylpiperidin-1-yl
6
O
O
O
O
R'
R'
Scheme 2 Previous approaches to tetrahydrofuran lignans III and the proposed
bioinspired strategy.
O
O
R'
8m R' = H,
8n R' = OMe, THF, 68%, dr 3:1
R'
Recently, we applied redox isomerizations8 as an atom-
economic reactive intermediate switch from alkoxide anions to
enolates. They served well in a unique tandem organometallic
8k R' = H,
8l R' = OMe, DME, 71%, dr 3:1
DME, 62%, dr 5:1
THF, 60%, dr 3:1
O
O
O
O
addition of aryllithium reagents
1
to
/redox isomerization of resulting alkoxide
/Michael addition to /radical cyclization/oxygenation
a
,
b
-unsaturated aldehydes
O
O
2
4
3
to enolate
5
O
O
O
O
process, providing diverse highly functionalized cyclopentane
O
O
TBS
TBS
derivatives 6 9
.
8o THF, 65%, dr 3:1
8p THF, 41%, dr 4.5:1
Based on our experience in merging polar and radical
processes,10 we hypothesized that a bioinspired radical-based
a General conditions: tBuLi (2.6 mmol), aryl halide (1.3 mmol) in THF or DME (8 mL),
–78 °C, 35 min; addition of 2 (1.3 mmol), 15 min, (p-cymene)ruthenium dichloride
dimer (0.026 mmol), P(OMe)3 (0.026 mmol), 5 min; 86 °C, typically 10-20 min; 7
(1.5 mmol), –78 °C.
modular strategy may provide
tetrahydrofuran lignans III. We envisaged a tandem process
consisting of nucleophilic addition of substituted aryllithiums
to unsaturated aldehydes and subsequent redox
isomerization of resulting alkoxides, thus generating enolates
a very short access to
1
2
With those catalytic conditions at hand, the scope of the
tandem addition/isomerization/coupling sequence was
4
.
Their single electron oxidation to radicals, similar to that of
2 | J. Name., 2012, 00, 1-3
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ARTICLE
explored using ferrocenium hexafluorophosphate13 as the likely based on the combination of enolate geometry and
View Article Online
DOI: 10.1039/C7OB02848B
oxidant (Table 1). Subjecting phenyllithium and aliphatic
unsaturated aldehydes
8a-d in good yields and surprisingly good 6-7:1 established that aryl ketone enolates exist in solution as
a
,
b
-
aggregation effects. We proved previously that the enolates 4
2
to the sequence gave 1,4-diketones are formed with exclusive (Z)-configuration.9 It has also been
diastereoselectivity for the coupling of these rather unbiased tetrameric aggregates.15 SET oxidation of the aggregate of
4
systems.11,14 THF or DME were used with similar results, but the leads to a tetrameric radical cation 13, in which three enolate
isomerization is faster in higher boiling DME. Cinnamic aldehyde units are positioned to add as nucleophiles. Since rotation
derivatives with variable substitution pattern at the aryl ring around the C-C bond in radical cation 13 is still hindered
were as well applicable furnishing 2,3-dibenzylic 1,4-diketones because of its partial double bond character, d/l-
8e-i with similar good diastereoselectivities. Even C-C bond formation and another SET oxidation step (not
polymerization-sensitive acrolein was applicable in the tandem shown). Minor meso- can form by slow rotation to (E)-radical
8 results after
8
reactions giving 8a,m-p with reasonable yields and cation 14 and intraaggregate coupling with surrounding enolate
diastereoselectivities. Non-commercial aryllithium reagents units. This proposal is strengthened by Flower’s results, who
were conveniently generated by lithium-halogen exchange of invoked aggregates in oxidative cross-coupling reactions with
the corresponding commercial aryl bromides with tert- simple pinacolone enolates.16 For oxygenated substrates 8m-p
,
butyllithium. They underwent the tandem reaction with similar alternative aggregate structures involving the phenolic units
results providing diketones 8k-p For most oxygenated can also be envisaged, in which the enolate units are not that
.
aryllithium substrates it was better to use THF as the solvent, well aligned for coupling, thus leading to lower diastereomeric
since the enolates tended to precipitate in DME thus thwarting ratios.
the subsequent SET oxidation. It was noted that additional
alkoxy substituents at the arene ring, such as in 8h, 8i and 8l-p,
led to somewhat decreased, but still reasonable 3-5:1
diastereoselectivities.
RuLnCl
O
OLi
Ar
R
2
+
1
H
Ar
R
9
3
The configuration of the minor 1,4-dicarbonyl compounds
meso-8d-g and that of major d/l-8g was unambiguously
determined by X-ray crystallography (Figure 1). On this basis,
the configuration of all other compounds was assigned by NMR
spectroscopy.
RuLnCl
O
H
LnRuCl2
Ar
Ar
LiCl
Ar
R
S
R
10
R
O
Li
O
S
R
Cl
H
Li
O
O
Li
LnRu
ORuLnCl
O
Li
R
S
Ar
R
Ar
R1
Ar
12
S
11
Ar
4
7
S = Solvent
Ar
Ar
Ar
Ar
S
R
S
R
R
S
R
O
Li
O
Li
O
S
R
Li
O
Li
O
Li
R
R
Li
O
Li
S
S
O
Li
O
Ar
Ar
R
S
S
14
13
Ar
Ar
7
7
O
O
O O
Fig. 1 Structure determination of the minor diastereomers of 8d, 8e, 8f, 8g and the major
diastereomer of 8g by X-ray crystallography. Displacement ellipsoids are drawn at 30%
probability level.
Ar
Ar
Ar
Ar
R
R
R
R
d,l-8
meso-8
The mechanistic course of the tandem reaction can be
Scheme
3 Mechanistic course of the tandem 1,2-addition/isomerization/radical
rationalized by nucleophilic 1,2-addition of aryllithiums
1
to
dimerization reactions.
unsaturated aldehydes generating allylic lithium alkoxides
2
3
(Scheme 3). In the presence of the ruthenium catalyst, alkoxide
transmetalates to ruthenium alkoxide , which presumably
forms oxygen-coordinated ruthenium hydride complex 10
which may be in equilibrium with the C-bound hydride complex
11. From both, hydride transfer to the -position proceeds,
generating ruthenium enolate 12, which transmetalates back to
the corresponding lithium enolate and regenerates the catalyst.
The surprising diastereoselectivity of the dimerization is most
The major d/l diastereomers of 1,4-diketones 8m-p are
convenient precursors for short total syntheses of
tetrahydrofuran lignans (Scheme 4). Reduction of all substrates
with excess lithium aluminum hydride in THF gave a crude
mixture of diols 15 in quantitative yields as a ca. 1:1.5:5-6
mixture of symmetrical and unsymmetrical diastereomers (For
a stereochemical rationale, see the ESI, Scheme S1). It must be
noted that many reduction and hydrogenation methods were
3
9
,
b
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tried, but only LiAlH4 at room temperature gave diols 15 without amounts of cis,trans,trans tetrahydrofuran lignans veraguensin
View Article Online
competing formation of lactols and derived side products.
(
17a), beilschmin B (17b), or unnamed 1D7OcI:w10e.1r0e39a/lCso7OisBo0l2a8t4e8dB.
When the crude mixture of diols 15m-o was subjected to BF3 The isolated amounts of dihydronaphthalenes 18a-c did not
as the Lewis acid at –78 °C the trans,trans,trans- change significantly compared to method A.
tetrahydrofuran lignans (±)-galbelgin (16a), (±)-grandisin (16b), The methodology was also applicable to the total synthesis of
or (±)-galbacin
(
16c
)
were isolated with 8-10:1 hydroxy group-containing lignans, such as fragransin A2 (16e),
diastereoselectivity over diastereomeric cis,trans,trans-17a-c when diketone 8p was used (Scheme 5). Its reduction followed
(Scheme 4; Method A). The dihydronaphthalene lignans 18a-c
,
by
cycloetherification
as
described
above
with
gave
good
which have also been isolated as natural products,17 were trans,trans,trans-tetrahydrofuran
16d
formed competitively in low yields. The formation of lignans diastereoselectivity in the presence of BF3•OEt2. In contrast,
under these reaction conditions is irreversible, since method B reproducibly gave low yields of tetrahydrofurans 16d
resubjecting them to BF3 under the reaction conditions did not and 17d, but a much larger proportion of dihydronaphthalene
lead to a change in the ratio (not shown).
18d
.
Applying
Mitsunobu
conditions18
for
the
cycloetherification proved to be more effective giving 16d and
17d in improved yield, but similar low diastereoselectivity as in
method B. Treatment of tetrahydrofurans 16d and 17d with
TBAF provided the natural products fragransin A2 (16e) and
odoratisol (17e) in quantitative yield.
O
O
(RO)n
(OR)n
(OR)n
Ar =
8m-o
LiAlH4, THF, rt
O
O
Ar
Ar
Ar
Ar
Ar
Ar
O
O
+
+
OH
OH
OH
OH
OH
OH
TBSO
OTBS
8p
15m-o quant, dr 1:5-6:1.5
LiAlH4, THF, rt, then
Method A or B or C
(cf. Scheme 4)
Method A or B
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
TBS
O
O
O
O
+
+
+
+
O
TBS
O
O
O
TBS TBS
TBS
O
O
16d
17d
18d
17a (±)-veraguensin
16a (±)-galbelgin
OTBS
18a (±)-Cyclogalgravin
A 55%, 10:1
B 32%, 3:1
C 62%, 2:1
A 14%, dr >20:1
B 40%, dr >20:1
2%, dr 2:1
A 14%, dr 10:1
B 11%, dr >20:1
TBAF, THF, rt
A 57%, 10:1
B 78%, 2:1
C
O
O
O
O
O
O
O
O
+
O
O
O
O
O
O
O
O
O
HO
OH
HO
OH
O
O
+
+
99%
17e (±)-odoratisol
16e (±)-fragransin A2
O
O
O
O
O
O
Scheme 5 Total synthesis of phenolic lignans fragransin A2 and odoratisol. For method A
and B, see Scheme 4; Method C: DIAD, PPh3, THF, 0 °C to rt.
O
17b (±)-beilschmin B
18b
16b (±)-grandisin
A 40%, 8:1
B 69%, 3:1
A trace
B 8%, dr >20:1
The good diastereoselectivity of the cycloetherification
reactions mediated by BF3•OEt2 despite the low 1:1.5:5-6
diastereomeric ratio of diols 15 deserves comment (Scheme 6).
The results indicate that it proceeds by a stereoconvergent SN1
mechanism, because the diastereomeric ratio of the starting
materials is not reflected in the products 16-18, as would be
expected in an SN2-type reaction. The Lewis acid BF3 abstracts
hydroxide to form quinoid carbenium ions 19. Whereas minor
anti,anti-15 can only cyclize via transition state
O
O
O
O
+
+
O
O
O
O
O
O
O
O
O
O
16c (±)-galbacin
(±)-17c
18c
A 62%, 8:1
B 70%, 2:1
B 58%, 3.5:1
A 14%, dr >20:1
B 14%, dr 17:1
B 13%, dr 11:1
(at –78 °C)
Scheme 4 Total synthesis of tetrahydrofuran lignans 16 and 17 by reduction and
cycloetherification. Method A: BF3•OEt2, CH2Cl2, –78 °C. Method B: MsCl, NEt3, CH2Cl2, 0
°C.
trans,trans,trans-19
, the anti-oriented hydroxy group is
apparently predominately activated in unsymmetrical anti,syn-
19 and cyclization also proceeds via trans,trans,trans-19 to
tetrahydrofuran 16. Only small amounts of THF 17 are formed
via transition state cis,trans,trans-19, which is higher in energy
because of the cis orientation of the arene and the methyl group
in the benzylic alcohol part. The minor dihydronaphthalene 18
likely results from cyclization of minor syn,syn-15. After
The
diastereoselectivity
for
the
formation
of
trans,trans,trans-16a-c was considerably lower, when the
cycloetherification was performed by mesylation and
intramolecular substitution reaction (Method B) and significant
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elimination of the hydroxy group,
ARTICLE
Friedel-Crafts-type They are easily transformed into the tetrahydrofuran core by
a
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cyclization via strain-free chair-type transition state reduction and cycloetherification, whicDhOIp: r1o0.c1e0e39d/Cw7OitBh02g8o4o8Bd
trans,trans,trans-20 predominates, thus avoiding energetically diastereoselectivity under SN1 conditions. These results are
higher cis-orientations in transition states, such as interesting with respect to the biosynthetic origin of
cis,trans,trans-19. In contrast, the cyclization of anti,anti- and tetrahydrofuran lignans, where carbocations are supposed to
anti,syn-15 to dihydronaphthalenes 18 is less likely, since a cis- be involved as in the presented results, suggesting that the
orientation of hydroxy and methyl groups in the transition state involved proteins enforce the conformation of the cyclizing
increase its energy (not shown).
substrate to the species-specifically formed stereochemically
diverse THF lignans.
Ar
Ar
Ar
Ar
Ar
Ar
+
+
OH
OH
OH
OH
OH
OH
Conflicts of interest
There are no conflicts to declare.
anti,anti-15m-p
anti,syn-15m-p
syn,syn-15m-p
–OH–
–OH–
–OH–
Acknowledgements
(OR)n
Ar
+
H
H
H
+
H
HO
Generous financial support by the Institute of Organic
Chemistry and Biochemistry of the Czech Academy of Sciences
(RVO:61388963), the Gilead Sciences Research Center at IOCB
and the Grant Agency of the Czech Republic (P203/09/1936) is
gratefully acknowledged. I.C. thanks the Ministry of Education,
Youth and Sports of the Czech Republic (MSM0021620857) for
financial support.
H
Ar
OH
OH
+
Ar
H
Ar
Ar
trans,trans,trans-19
cis,trans,trans-19
trans,trans,trans-20
–H2O
(OR)n
+
+
Ar
Ar
Ar
Ar
O
O
Ar
18
16
17
Notes and references
Scheme 6 Stereochemical rationale for the BF3•OEt2-mediated cycloetherification
reactions of diastereomeric diols 15.
1
(a) S. Suzuki and T. Umezawa, J. Wood Sci., 2007, 53, 273-284;
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The diastereoselectivity of the cycloetherification via the
intermediate mesylate (Method B)4,19 or using the Mitsunobu
conditions (Method C) is in contrast more in line with an SN2
mechanism, since the configuration of diols 15 is well reflected
in the products 16 and 17 (For a rationalization see the ESI,
Scheme S2). This reasoning is also supported by the fact that the
diastereoselectivity of the cycloetherification remains similar
on lowering the temperature to –78 °C and remains significantly
different from that of the BF3-mediated cyclization. These
results are important concerning the biosynthetic origin of the
stereochemically diverse tetrahydrofuran lignans (cf. Scheme
1), since the results point to the fact that the configuration of
the natural products is not determined by the unconstrained
conformational preferences of the carbocationic intermediates
as described here, but rather by the conformation enforced by
the involved dirigent protein or enzyme.2,20
Adv., 2017, 7, 46932-46937.
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construction of the carbon framework is the new tandem
nucleophilic addition/ruthenium-catalyzed isomerization/SET
oxidation/radical dimerization resulting in 1,4-dicarbonyl
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Organic & Biomolecular Chemistry
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Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C7OB02848B
Three steps suffice to complete a bioinspired total synthesis of tetrahydrofuran lignans using
tandem addition/isomerization/dimerization and cycloetherification reactions.
R
8
Biosynthesis
8,8'-Coupling
Three
steps
H2O
+
Ar
Ar
O
O
R = H, OH
ArLi
OCH3
(OR)n
OH
Ar =