A bio-inspired total synthesis of tetrahydrofuran lignans

Article abstract of DOI:10.1002/anie.201408641

Lignan natural products comprise a broad spectrum of biologically active secondary metabolites. Their structural diversity belies a common biosynthesis, which involves regioand chemoselective oxidative coupling of propenyl phenols. Attempts to replicate this oxidative coupling have revealed significant challenges for controlling selectivity, and these challenges have thus far prevented the development of a unified biomimetic route to compounds of the lignan family. A practical solution is presented that hinges on oxidative ring opening of a diarylcyclobutane to intercept a putative biosynthetic intermediate. The effectiveness of this approach is demonstrated by the first total synthesis of tanegool in 4 steps starting from ferulic acid, as well as a concise synthesis of the prototypical furanolignan pinoresinol.

Full text of DOI:10.1002/anie.201408641

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Chemie
DOI: 10.1002/anie.201408641
Total Synthesis
A Bio-Inspired Total Synthesis of Tetrahydrofuran Lignans**
Anna K. F. Albertson and Jean-Philip Lumb*
Abstract: Lignan natural products comprise a broad spectrum
of biologically active secondary metabolites. Their structural
diversity belies a common biosynthesis, which involves regio-
and chemoselective oxidative coupling of propenyl phenols.
Attempts to replicate this oxidative coupling have revealed
significant challenges for controlling selectivity, and these
challenges have thus far prevented the development of a unified
biomimetic route to compounds of the lignan family. A
practical solution is presented that hinges on oxidative ring
opening of a diarylcyclobutane to intercept a putative biosyn-
thetic intermediate. The effectiveness of this approach is
demonstrated by the first total synthesis of tanegool in 4 steps
starting from ferulic acid, as well as a concise synthesis of the
prototypical furanolignan pinoresinol.
T
he biosyntheis of lignan natural products is characterized
by an exceptionally efficient increase in molecular complex-
ity. From only a handful of relatively simple propenyl phenols,
plants derive a complex array of secondary metabolites that
include 4-, 6-, 7-, and 8-membered carbocycles, linear
dibenzylbutanes, and diversely substituted tetrahydrofurans
(Scheme 1a).[1–3] In plants, lignans are a front-line chemical
defense against pathogens, while their anticancer, antimitotic,
antiangiogenesis, and antiviral activities have made them the
focal point of traditional and pharmaceutical medicine.[4]
Despite their structural diversity, lignan biosynthesis is
believed to occur through a common oxidative coupling of
propenyl phenols to afford a key bis-para-quinone methide
(3; Scheme 1b). Hydration, reduction, or cyclization of 3
gives rise to parent lignan scaffolds that are further tailored
through a range of transformations.[1d] Given the uniformity
of lignan bioysnthesis, the direct oxidative coupling of
propenyl phenols has been the subject of extensive biomim-
etic studies, dating to the early work of Haworth and co-
workers in the 1940s.[5] These, and many subsequent exam-
ples,[6] have underscored the difficulties of controlling regio-
À
and stereoselectivity during C C coupling, and chemoselec-
Scheme 1. a) Structural diversity of the lignan family of natural prod-
tivity between oxidation of the starting phenol and over-
oxidation of the product. In 1997, Lewis and co-workers
elegantly demonstrated that selectivity during biosynthesis
ucts. b) Proposed biosynthesis through oxidative coupling. c) Bio-
inspired synthesis through oxidative ring opening of a diarylcyclobu-
tane.
[*] A. K. F. Albertson, Prof. J.-P. Lumb
Department of Chemistry, McGill University
801 Sherbrooke Street West, Montreal, QC, H3A 0B8 (Canada)
E-mail: jean-philip.lumb@mcgill.ca
could be controlled by a rather unique dirigent protein, in the
presence of which the one-electron oxidation of coniferyl
alcohol (1) afforded (+)-pinoresinol (4).[7,8] While of funda-
mental importance to understanding their biosynthesis, the
discovery of dirigent proteins has not yet had a practical
impact on the laboratory synthesis of lignans, for which
a robust and unified bio-inspired approach has not been
reported.
[**] We thank Prof. James Gleason for numerous insightful discussions.
Financial support was provided by the Natural Sciences and
Engineering Council of Canada (Discovery Grant to J.P.L.), the
Fonds de Recherche du Quꢀbec—Nature et Technologies (Nou-
veaux Chercheur Grant to J.P.L), and McGill University.
Supporting information for this article (including experimental
details) is available on the WWW under http://dx.doi.org/10.1002/
anie.201408641.
The challenges of controlling selectivity in the oxidative
coupling of 1 prompted us to consider an alternative approach
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to quinone methide 3 that hinges on the oxidative ring
opening of diaryl cyclobutane 5 (Scheme 1c). Strategically,
this reverses the steps of coupling and oxidation, such that
issues of regio- and stereoselectivity are first addressed in
a [2+2]-cycloaddition. The involvement of diaryl cyclobu-
tanes in the biosynthesis of aryltetralin lignans was initially
discussed by Kikuchi[9] and Wilson[10] and their co-workers,
who showed that a one-electron oxidation initiated a 4- to 6-
membered-ring expansion, albeit with poor efficiency owing
to competitive cycloreversion.[11–13] The key intermediate in
this rearrangement, a delocalized radical cation, has been the
topic of extensive investigations, which have helped to shape
our understanding of radical-ion reactivity.[14–16] In the very
different context of aminoimidazole alkaloid biosynthesis,
Molinski[17] and Baran[18] and their co-workers have discussed
and implemented a related ring expansion of the cyclobutane
sceptrin, thus highlighting close similarities in the potential
biosynthetic strategies of two very different organisms. In the
current work, we demonstrate that the selective oxidation of
diarylcyclobutanes with free phenols leads to an efficient,
divergent, and robust bio-inspired synthesis of furanolignans.
Whereas the oxidative coupling of propenyl phenols
remains nonselective, significant progress has been made in
the corresponding photochemical [2+2] cycloaddition of
cinamic acids and esters.[19–21] In the solution phase, their
photochemistry is dominated by olefin isomerization, but
irradiation of the appropriate polymorph in the solid state
leads to selective cycloaddition.[22] The rules governing the
selectivity and efficiency of head-to-head versus head-to-tail
coupling have been extensively studied by Schmidt and co-
workers[22,23] and were recently exploited by Kibayashi and
co-workers in the total synthesis of incarvillateine.[24] We
began by optimizing the [2+2] photodimerization of para-
nitro-ferulate ester 7 through irradiation of a suspension in
hexanes with a medium-pressure mercury lamp (Scheme 2a).
Reduction of the crude material with lithium aluminum
hydride completed a 3-step synthesis of diarylcyclobutane
diol 8, which proceeded in an overall yield of 74% on a 10 g
scale (see the Supporting Information for details).
We began our investigation into the oxidative ring open-
ing of 8 with phenyliodo diacetate (PIDA) and were
encouraged to isolate the natural product (Æ)-tanegool[25] as
a single diastereomer in yields of up to 40% (Scheme 2a).
Under optimized conditions, a homogeneous solution of
PIDA in trifluoroethanol was added dropwise to a solution of
8 in acetone at À408C. Presumably, this leads to oxonium ion
10 following two-electron oxidation,[26] which triggers scission
of the cyclobutane to provide benzylic carbocation 11. Loss of
acetic acid then generates bis-para-quinone methide 12,
which is a presumed biosynthetic intermediate. To obtain
Scheme 2. 4-Step synthesis of (Æ)-tanegool from ferulic acid. a) Oxidation mediated by phenyliodo diacetate (PIDA) at À408C. b) Oxidation
mediated by iron trichloride hexahydrate (FeCl3·6H2O) at 08C.
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our highest yields of 9, we delayed the addition of H2O as a 1:1
mixture in THF until the consumption of PIDAwas complete.
We believe that this sequential addition of H2O prevents the
over-oxidation of 9 by keeping the reaction at the stage of
para-quinone methide 12 until complete consumption of the
oxidant. Subsequent 5-exo-trig cyclization of the 18 alcohol
leads to (Æ)-tanegool (9) after hydration of 13. The anti
relationship between the aromatic ring and the hydroxy-
methyl substituent in 13 reflects a kinetic bias for the
cyclization of rotamer 12a over 12b, in which the para-
quinone methide adopts a conformation that minimizes allylic
strain.
Since the yield of 9 could not be improved beyond 40%
with IIII-based oxidants, we investigated iron trichloride
hexahydrate (FeCl3·6H2O) as an alternative one-electron
oxidant (Scheme 2b). Whereas PIDA likely proceeds through
the ring opening of oxonium ion 10,[26] FeCl3 has the potential
to promote a radical-based mechanism for ring opening via 14
or the corresponding arene radical cation.[10,12] Gratifyingly,
the addition of an aqueous solution of FeCl3·6H2O to
a solution of 8 in acetone at 08C dramatically improved the
mass balance of the reaction and afforded a 59% yield of (Æ)-
tanegool (9) along with its C7’ epimer 15 in 14% yield at 83%
conversion.[27] Selectivity for (Æ)-tanegool could be restored if
the oxidation was buffered with an amine base, and exposure
of pure 9 to aqueous hydrochloric acid (HCl) led to a 2:1
mixture with 15 after 20 h at RT. These results, along with the
complete absence of 15 when 8 is oxidized with PIDA, suggest
a kinetic bias for the formation of 9 during the cyclization/
hydration of quinone methide 12, which then isomerizes to 15
in the presence of acid. Among the four possible diastereo-
mers that can form from quinone methide 12, (Æ)-tanegool
(9) and diastereomer 15 are the only two that have been
reported as natural products.[25,28] Interestingly, both are
isolated in enantioenriched form, thus suggesting that enan-
tioselective cyclization of 12 may occur during biosynthesis.
Whether dirigent proteins can fulfill this function is an
intriguing question, since they have traditionally been asso-
ciated with the oxidative coupling of propenyl phenols[7,8] but
not with the subsequent cyclization of the para-quinone
methides.
While the tanegool diastereomers originate from the
desymmetrization of the S2-symmetric conformation of para-
quinone methide 12, pinoresinol (4) and many related lignans
possess a syn configuration at C2 and C3 of the THF ring
(Scheme 3a), which requires cyclization of a C2-symmetric
para-quinone methide 16. The distinction between isomeric
para-quinone methides 12 and 16 has been discussed in the
context of the direct oxidative coupling of coniferyl alcohol
(1), which favors 16 in the presence of a dirigent protein, but is
nonselective otherwise.[29] In principal, 16 should be accessible
from the oxidative opening of C1-symmetric cyclobutane diol
17 by following our approach. Thus, desymmetrization of
a suitably protected meso-cylobutane diester 18 by enoliza-
tion and protonation affords the trans-diester 19 (Scheme 3b),
which is readily converted to trans-cyclobutane diol 20
following reduction and deprotection. Subsequent oxidation
with FeCl3·6H2O under our previously optimized conditions
affords (Æ)-pinoresinol (4) in 48% yield (87% based on
Scheme 3. Synthesis of (Æ)-pinoresinol. a) Stereochemical analysis of
of tanegool and pinoresinol. b) Bio-inspired synthesis of pinoresinol
(4).
recovered starting material), wherein the relative configura-
tion at C2 and C3 of the cyclobutane is relayed to the cis-fused-
5,5-ring juncture of the natural product. As with the cycliza-
tion of 12a during the synthesis of (Æ)-tanegool (Scheme 2),
the 5-exo-trig cyclization of bis-para-quinone methide 21 is
selective for the rotamer that places the quinone methide in
a sterically favored syn conformation relative to the hydrogen
atom at C2. This gives rise to 22, which undergoes a second 5-
exo-trig cyclization with the expected stereoselectivity. This
completes the synthesis of (Æ)-pinoresinol by installing the
cis-fused 5,5-ring system and underscores the principal
distinction between the oxidation of cyclobutane diols 8 and
20. In the oxidation of 8, a second 5-exo-trig cyclization at the
stage of 13 is either precluded or thermodynamically disfa-
vored by the trans-configuration at C2 and C3, which would
produce a strained 5,5-trans-fused product.
In summary, we have developed a concise approach to the
furanolignans, which hinges on the oxidative opening of
diarylcyclobutane diols. The resulting para-quinone methides,
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Revised: October 17, 2014
Published online: && &&, &&&&
Keywords: biomimetic synthesis · cascade reactions · lignans ·
.
natural products · phenolic oxidation
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Communications
Total Synthesis
A. K. F. Albertson,
J.-P. Lumb*
&&& — &&&
A Bio-Inspired Total Synthesis of
Tetrahydrofuran Lignans
Ringing the changes: A bio-inspired syn-
thesis of furanolignan natural products
that hinges on the oxidative ring opening
of diarylcyclobutane diols is reported. The
resulting bis-para-quinone methides par-
ticipate in a complex cascade to complete
the first total synthesis of tanegool.
Modification of the cyclobutane prior to
oxidation affords the structurally distinct
lignan pinoresinol, thus demonstrating
the flexibility of this synthetic strategy.
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