Total synthesis of kingianinsA, D, and F

Article abstract of DOI:10.1002/anie.201210084

A synthesis fit for a king: The total synthesis of (±)-kingianinsA, D, and F has been achieved in ten steps. Key features include the gram-scale synthesis and partial reduction of a conjugated tetrayne to a (Z,Z,Z,Z)-tetraene, the domino 8π-6π electrocyclic ring closure of a (Z,Z,Z,Z)-tetraene, and the radical-cation-catalyzed formal Diels-Alder dimerization of functionalized bicyclo[4.2.0]octadiene precursors. Copyright

Full text of DOI:10.1002/anie.201210084

Angewandte
Chemie
DOI: 10.1002/anie.201210084
Biomimetic Synthesis
Total Synthesis of Kingianins A, D, and F**
Samuel L. Drew, Andrew L. Lawrence,* and Michael S. Sherburn*
In Memory of Rodney W. Rickards
The kingianin natural products are a unique group of complex
racemic bicyclo[4.2.0]octadiene dimers, isolated from the
bark of Endiandra kingiana (Lauraceae) by Litaudon and co-
workers.[1] The first reported kingianin, (Æ)-kingianin A
(1),[1a] formulates as a dimer of bicyclo[4.2.0]octadiene 2,
and the Litaudon group proposed a biosynthesis involving
a radical cation Diels–Alder dimerization could explain the
formation of the kingianins in nature.
The bicyclo[4.2.0]octadiene framework present within
Litaudonꢀs proposed biosynthetic monomer 2 is a skeletal
feature found in several natural products.[5–9] The endiandric
acids, which were isolated in racemic form in the early 1980s
by Black and colleagues, were the first reported examples.[5]
Scheme 2. The 8p–6p biosynthesis of bicyclo[4.2.0]octadiene struc-
tures, as proposed by Black et al.[5b–f]
Scheme 1. Diels–Alder biosynthetic pathway to (Æ)-kingianin A (1), as
Black proposed that the bicyclo[4.2.0]octadiene structure was
formed through a spontaneous 8p–6p domino electrocycliza-
tion of either an (E,Z,Z,E)-tetraene or a (Z,Z,Z,Z)-tetraene
(Scheme 2).[5b–f] Beautiful biomimetic syntheses of various
bicyclo[4.2.0]octadiene natural products by Nicolaou,[10] Trau-
ner,[11] Baldwin,[12] Parker,[13] and Moses[14] have successfully
utilized the proposed (E,Z,Z,E)-tetraene precursors. Evi-
dently, the difficulty associated with preparing conjugated all-
(Z)-polyenes has precluded their use in synthesis. In fact,
(2Z,4Z,6Z,8Z)-decatetraene is both the highest all-(Z)-con-
jugated polyene and the only (Z,Z,Z,Z)-tetraene synthesized
thus far.[15]
Given the unprecedented structure and puzzling biosyn-
thetic origin of the kingianin natural products,[1] we decided to
embark upon efforts towards their synthesis. The wealth of
synthetic work in the literature utilizing (E,Z,Z,E)-tetraene
precursors to access bicyclo[4.2.0]octadiene structures[3,10–14]
convinced us that we should take this opportunity to
investigate the alternative biosynthetic precursor, namely
the (Z,Z,Z,Z)-tetraene (Scheme 2).[5b–f] Although initially
drawn to the sp2–sp2 cross-coupling strategy utilized by
Negishi for the synthesis of (Z,Z,Z)-trienes,[16] we elected
instead to investigate the feasibility of a four-fold stereo-
selective partial reduction of a conjugated tetrayne. We
anticipated that if this unprecedented[17] and highly challeng-
ing[18] synthetic transformation were realized then a remark-
ably short synthesis of the kingianins could be achieved.
The application of previously reported methods[19] for the
synthesis of unsymmetrical tetraynes was met with great
difficulties. The instability of the requisite intermediates and
problems associated with scaling up these approaches led us
to develop a new scalable synthesis of unsymmerical tet-
proposed by Litaudon et al.[1]
spontaneous (non-enzyme-mediated) Diels–Alder dimeriza-
tion (Scheme 1).[1] Several reports, however, describe the
need for temperatures in excess of 1508C for Diels–Alder
dimerization of 1,3-cyclohexadiene.[2] The notion that a struc-
tural feature within compound 2 may lower the barrier to
thermal Diels–Alder dimerization was investigated by Moses
and co-workers in 2011.[3] An elegant synthesis of monomer 2
was achieved by the Moses group, but all attempts to induce
thermal dimerization failed.[3] Inspired by the pioneering
work of Bauld and co-workers,[4] we hypothesized that
[*] S. L. Drew, Dr. A. L. Lawrence, Prof. M. S. Sherburn
Australian Research Council Centre of Excellence for Free Radical
Chemistry and Biotechnology, Research School of Chemistry,
Australian National University
Canberra, ACT 0200 (Australia)
E-mail: allawrence@rsc.anu.edu.au
sherburn@rsc.anu.edu.au
[**] This work was supported by the Australian Research Council. A.L.L.
gratefully acknowledges financial support from the Australian
Research Council in the form of a Discovery Early Career Researcher
Award (DE120102113). S.L.D. gratefully acknowledges financial
support from the Rickards family through the Rodney Rickards
Scholarship. We thank Prof. Litaudon (CNRS, France) for kindly
providing copies of the original NMR data. We also thank Mr. Tony
Herlt (ANU) for assistance with HPLC and Mr. Chris Blake (ANU)
for NMR measurements.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201210084.
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raynes. It is well known that steric bulk can stabilize polyyne
structures.[20] We took advantage of this fact by targeting TBS-
protected (TBS = tert-butyldimethylsilyl) alcohol tetrayne
3,[21] using Mori–Hiyama conditions for TMS-alkyne
(TMS = trimethylsilyl) dimerization,[22] thereby avoiding
unstable halogenated and terminal polyynes. The two requi-
site diynes 4 and 5 were successfully prepared in three and two
steps, respectively, on a multi-gram scale (Scheme 3). Thus, an
Alami modified[23] Cadiot–Chodkiewicz coupling of known
bromobutynol 6[24] with ethynyltrimethylsilane afforded
TMS-diyne 7, which was converted into TBS-ether 4 under
standard conditions.[25] Meanwhile, known benzyl bromide
8[26] was employed in a Negishi reaction[27] with organozinc
reagent 9,[28] which was derived from 1,4-bis(trimethylsilyl)-
buta-1,3-diyne.[29] Following extensive optimization, tetrayne
3 was isolated in 40% yield on a gram scale.[30] This is the first
reported crossed Mori–Hiyama coupling reaction[22] and the
first gram-scale synthesis of an unsymmetrical tetrayne.[19]
With significant quantities of tetrayne 3 now available,
investigation into the daunting four-fold reduction could
begin.[17,18] Following extensive experimentation, it was found
that Rieke zinc in ethanol afforded (Z,Z,Z,Z)-tetraene 10 in
a completely chemoselective and highly diastereoselective
manner (Scheme 4).[17,31] A solution of tetraene 10 in toluene
was immediately heated to 1008C, which triggered the
domino 8p–6p electrocyclization sequence.[32] Following
deprotection, the two diastereomeric alcohols 11 and 12
were isolated in a combined yield of 21% from tetrayne 3
(Scheme 4).
Scheme 3. Gram-scale synthesis of unsymmetrical tetrayne 3.
dppf=1,1’-bis(diphenylphosphino)ferrocene, NBS=N-bromosuccini-
mide, TBS=tert-butyldimethylsilyl, TMS=trimethylsilyl.
We were delighted to find that both alcohols 11 and 12
underwent fast radical cation Diels–Alder dimerizations
using catalytic quantities of the Ledwith–Weitz aminium
salt, (p-BrC6H4)3N·SbCl6 (13; Scheme 4).[33] Amide 2, the
proposed biosynthetic precursor to (Æ)-kingianin A (1),[1a]
Scheme 4. Completion of the total synthesis of (Æ)-kingianins A, D, and F. EDC=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, HOBt=hydrox-
ybenzotriazole, NMO=N-methylmorpholine-N-oxide, TBAF=tetrabutylammonium fluoride, TPAP=tetrapropylammonium perruthenate.
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Justus Liebigs Ann. Chem. 1932, 496, 197; c) D. Valentine, N. J.
failed to dimerize under these reaction conditions
(Scheme 4).
Turro, Jr., G. S. Hammond, J. Am. Chem. Soc. 1964, 86, 5202;
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7586.
The synthesis of (Æ)-kingianins A (1) and D (14) was
eventually optimized to a sequence involving oxidation of
alcohol 11 using the tetrapropylammonium perruthenate/
N-methylmorpholine-N-oxide (TPAP/NMO) conditions of
Stark et al.,[34] with the product directly subjected to radical
cation Diels–Alder dimerization using the Ledwith–Weitz salt
(13; 5 mol%).[4,33] The resultant mixture of diastereomeric
diacids was directly converted into the corresponding dia-
mides. Column chromatography afforded a mixture of three
dimeric diamides in 17% yield over the three steps from
alcohol 11. Reverse-phase preparative HPLC allowed the
isolation of analytically pure samples of (Æ)-kingianin A (1),
(Æ)-kingianin D (14) and a third, as yet undetermined,
structure.[1] This radical cation Diels–Alder dimerization is
a remarkably selective reaction, with only three of the
potential thirty-two isomeric products isolated. Both (Æ)-
kingianin A (1), a homochiral dimer, and (Æ)-kingianin D
(14), a heterochiral dimer, are the result of endo-selective
formal Diels–Alder reactions occurring at the convex faces of
both diene and dienophile. Previous studies have shown that
the radical cation Diels–Alder dimerization of 1,3-cyclohexa-
diene is endo selective,[4] however, a full explanation of the
site and orientational regioselectivity observed in the present
study will require further investigation. The natural product
(Æ)-kingianin F (15) was similarly obtained by dimerization
of the other bicyclo[4.2.0]octadiene diastereomer 12, followed
by double oxidation and diamide formation.[35]
In summary, our highly divergent biomimetic strategy has
resulted in the total synthesis of (Æ)-kingianins A (1), D (14)
and F (15), in a longest linear sequence of ten steps. The
noteworthy synthetic aspects of our successful approach
include the gram-scale preparation of an unsymmetrical
tetrayne, the unprecedented reduction of a conjugated tet-
rayne to a (Z,Z,Z,Z)-tetraene, and radical cation Diels–Alder
dimerization of functionalized bicyclo[4.2.0]octadienes. From
these studies, we conclude that the kingianins are not formed
through spontaneous Diels–Alder dimerization. Instead, we
propose that nature uses a SET-mediated cycloaddition
analogous to the approach described herein.[36,37] Our results,
in conjunction with previous biomimetic syntheses,[3,10–14]
demonstrate that (E,Z,Z,E)-tetraenes, and not their all-
(Z) congeners,[32] are the likely biosynthetic precursors to
bicyclo[4.2.0]octadiene natural products.[38]
[3] P. Sharma, D. J. Ritson, J. Burnley, J. E. Moses, Chem. Commun.
2011, 47, 10605. No spontaneous dimerization of compounds 2,
11, 12 (or the corresponding oxidation products) was observed
during the present study (see the Supporting Information for
details), nor has any spontaneous dimerization of any bicyclo-
[4.2.0]octadiene ever been reported.
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Published online: March 6, 2013
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Keywords: biomimetic synthesis · domino reactions ·
.
natural products · polyynes · radical cations
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