Total synthesis of ramonanins A-D

Article abstract of DOI:10.1002/anie.201409818

The first total synthesis of the ramonanin family of lignan natural products is described. The short synthesis involves a 2,5-diaryl-3,4-dimethylene tetrahydrofuran intermediate, which participates in an unexpectedly facile Diels-Alder dimerization, gener

Full text of DOI:10.1002/anie.201409818

Angewandte
Chemie
DOI: 10.1002/anie.201409818
Total Synthesis
Total Synthesis of Ramonanins A–D**
Ross S. Harvey, Emily G. Mackay, Lukas Roger, Michael N. Paddon-Row,*
Michael S. Sherburn,* and Andrew L. Lawrence*
Abstract: The first total synthesis of the ramonanin family of
lignan natural products is described. The short synthesis
involves a 2,5-diaryl-3,4-dimethylene tetrahydrofuran inter-
mediate, which participates in an unexpectedly facile Diels–
Alder dimerization, generating all four natural products.
Insights into the reactivity and stereoselectivity of the key
dimerization are provided through computational studies
employing B3LYP/6-31G(d) and M06-2X/6-31G(d) model
chemistries.
G
uaiacum officinale and Guaiacum sanctum are the sources
of the highly prized lignum vitae wood, known for its
extraordinary strength and durability. The resin of lignum
vitae, known as gum guaiac, or guaiac resin, is also valuable. It
is reported to possess various medicinal properties,[1] and has
also found application in colorimetric tests for oxidative
conditions (e.g., Noblesꢀ test,[2] Guaiac occult blood test,[3] and
Schçnbein–Pagenstecher test[4]). a-Guaiaconic acid (1) is the
constituent of gum guaiac that is readily oxidized, forming the
vividly colored guaiacum blue (2; Scheme 1a).[5] Sadly, the
highly sought-after attributes of lignum vitae wood and gum
guaiac have led to overexploitation of Guaiacum officinale,
which is now listed as an endangered species on the Red List
of the International Union for the Conservation of Nature.[6]
The ramonanins A–D (3–6) are a group of spirocyclic
phenylpropanoid tetramers isolated from the heartwood of
Guaiacum officinale by Schroeder and co-workers in 2011
(Scheme 1b).[7] The ramonanins (3–6) formulate as dimers of
a-guaiaconic acid (1) and are reported to exhibit cytotoxic
[*] R. S. Harvey, E. G. Mackay, L. Roger, Prof. M. S. Sherburn
Research School of Chemistry, Australian National University
Canberra, ACT 2601 (Australia)
Scheme 1. a) The structure and reactivity of a-guaiaconic acid (1).
b) Schroeder’s proposed biosynthesis of the ramonanins A–D (3–6).[7]
E-mail: michael.sherburn@anu.edu.au
activity against human breast cancer cell lines.[7] The endan-
gered status of Guaiacum officinale, together with the
promising biological activity of its natural products, are
classic motivations for total synthesis efforts.[8] In truth,
however, our attention was drawn to these molecules because
of their intriguing structures, which are fascinating from both
a topological and biosynthetic perspective. The spirocyclic
core of the ramonanins is unprecedented among natural
products and Schroeder and co-workers proposed a biosyn-
thetic pathway that involved dimerization of a lignan pre-
cursor, 7, through a “Diels–Alder-like mechanism” (Scheme
1b).[7]
Schroeder’s proposed biosynthetic intermediate 7 pre-
sumably also serves as the biosynthetic precursor to a-
guaiaconic acid (1). There are no reports of 1,2-dimethylene-
cyclopentane-type structures undergoing Diels–Alder dime-
rizations under ambient conditions.[9] It is, therefore, reason-
Prof. M. N. Paddon-Row
School of Chemistry, The University of New South Wales
Sydney, NSW 2052 (Australia)
E-mail: m.paddonrow@unsw.edu.au
Dr. A. L. Lawrence
School of Chemistry, The University of Edinburgh
Joseph Black Building, West Mains Road, Edinburgh, EH9 3JJ (UK)
E-mail: a.lawrence@ed.ac.uk
[**] This work was supported by the Australian Research Council and
a Marie Curie Career Integration Grant. M.N.P.-R. acknowledges
that this research was undertaken with the assistance of resources
provided at the NCI National Facility through the National
Computational Merit Allocation Scheme supported by the Austral-
ian Government. The authors thank Prof. Schroeder (Cornell
University) for kindly supplying samples of the ramonanin natural
products and Tony Herlt (Australian National University) for
assistance with HPLC separations.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201409818.
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Scheme 2. Synthesis of lignan 7.
able to assume that lignan 7 would not undergo a spontaneous
Diels–Alder dimerization.[10] Our previous studies on the
kingianin natural products utilized a radical-cation-catalyzed
formal Diels–Alder (RCDA) reaction to dimerize a thermally
unreactive bicyclo[4.2.0]octadiene structure.[11] We consid-
ered that the ramonanins A–D (3–6) might also be the result
of a biosynthetic RCDA dimerization.[12] To investigate the
nature of this fascinating biosynthetic dimerization we chose
to pursue a total synthesis of the ramonanin natural products
(3–6).[13]
The synthesis began with the high yielding conversion of
vanillin into its benzene sulfonate ester, a process that could
be easily conducted on large scale (Scheme 2). Two molecules
of the resulting aldehyde 8 were united through an acetylene
unit in a one-pot sequence to afford multigram quantities of
diacetate 9 as a 1:1 mixture of diastereomers. Following
a strategy pioneered by Mori and co-workers,[14] alkyne 9 was
subjected to an enyne metathesis with ethylene using the
Hoveyda–Grubbs II catalyst, to afford diene 10 on multigram
scale. Deprotection of the secondary alcohols was accom-
plished using KOH in MeOH to afford diol 11. Camphor
sulfonic acid was then used to promote 3,4-dimethylene
tetrahydrofuran ring formation, which generated protected
lignan 12 as a 2:1 mixture of diastereomers, both of which
would be required for the synthesis of ramonanins A–D (3–6).
This short synthetic sequence allowed access to multigram
quantities of key intermediate 12, which could be stored at
À158C for weeks without deterioration. When required, the
benzene sulfonate protecting groups could be cleanly
removed with NaOH in MeOH/THF to afford lignan 7
(Scheme 2).
Scheme 3. Dimerization of lignan cis-7.
allowed the isolation of analytically pure samples of ramona-
nins A–C (3–5) and the spectroscopic data for each synthetic
compound matched those reported for the corresponding
natural product, thus securing the total synthesis of ramona-
nins A–C (3–5). Optical rotation values for the natural
22
products were reported in the isolation paper [3: [a]D À2.2
22
22
(c 0.6, MeOH); 4: [a]D À4.0 (c 0.2, MeOH); 5: [a]D À5.2 (c
0.2, MeOH); 6: [a]D À5.1 (c 0.3, MeOH)].[7] Nevertheless,
22
since ramonanins A–C are the Diels–Alder dimers of the
achiral diene cis-7, we strongly suspected that these natural
products were racemates. To test this hypothesis, we per-
formed chiral HPLC analysis on samples of ramonanins A
and C, kindly provided by Professor Schroeder,[18] which
confirmed their racemic nature.
To our surprise and delight, dimerization of lignan 7 was
observed to occur spontaneously at room temperature, albeit
slowly.[15] Under optimized conditions, dissolution of the
monomer cis-7[16] in a minimal amount of DMF and warming
at 508C provided, after chromatographic purification,
a 54:9:37 mixture of ramonanins A (3), B (4), and C (5) in
a combined yield of 45%, in addition to 24% recovered
starting material cis-7 (Scheme 3).[17] Preparative HPLC
Our attention now turned to the final member of the
family: ramonanin D (6; Scheme 1). A unique stereochemical
feature of ramonanin D (6) is the trans relationship between
the two aryl substituents on the dihydrofuran ring. As would
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Table 1: B3LYP/6-31G(d) and experimental product distributions [%] for
the Diels–Alder dimerization of 13 and cis-7, respectively.
Adduct Mode Predicted Total predicted Experimental
Naa
Xsa
58.6
0.1
ram A
ram B
ram C
ramnoe
59
4
54
9
Nas
Xss
3.7
0
Nsa
Xaa
17.4
17.8
35
2
37
–
Nss
Xas
0.1
2.3
Alder’s endo rule. TSs with all phenyl groups positioned in the
syn space, are 16 (Nss) and 24 kJmolÀ1 (Xss) above the Naa
TS, reflecting steric congestion of the phenyl groups, as may
be seen by comparing the geometries of Naa and Nss TSs in
Figure 1. All TSs were found to be highly asynchronous, with
the shorter of the newly formed bonds between 1.72 and
1.97 ꢁ and the longer one between 3.04 and 3.69 ꢁ, the most
asynchronous being the Nss TS (Dr= 1.97 ꢁ, Figure 1).
Scheme 4. The eight stereoisomeric TSs for the dimerization of 13 to
afford the ramonanin simulacra (ram A, ram B, ram C, and ramnoe),
with explanation of the TS notation.
be expected, upon warming a mixture of cis-7 and trans-7,
complex mixtures of products were obtained. Nevertheless,
an analytically pure sample of ramonanin D (6) was isolated,
albeit in low (< 1%) yield, after multiple HPLC purification
steps.
Given the surprisingly facile nature of the Diels–Alder
dimerization of cis-7, we chose to investigate the reactivity
and stereochemical control of this process computationally,
using the B3LYP/6-31G(d) and M06-2X/6-31G(d) model
chemistries. The 2,5-diphenyl analogue of cis-7, namely 13
(Scheme 4), was used as a simulacrum.[19] Eight distinct
stereochemical modes of the Diels–Alder dimerization, and
hence eight transition structures (TSs), are possible, and these
are depicted in Scheme 4. The TSs are described using
a notation, in which the Alder–Stein mode may be either endo
(N) or exo (X) and the pair of phenyl substituents on the
diene and on the dienophile may be either anti (a) or syn (s)
with respect to the bond-forming zone. The eight TSs
comprise four pairs, both members of each pair giving one
of the ramonanin simulacra adducts (ram X = simulacra of
ramonanin X; ramnoe = not observed experimentally).
The computed product distribution for the Diels–Alder
dimerization of 13 is presented in Table 1, together with the
experimentally determined product distribution from dimer-
ization of cis-7 (Scheme 3). The agreement between the
predicted and experimental adduct distribution is good and
strongly suggests that not only is the model chemistry used in
this study reliable, but also that the OH and OMe substituents
in cis-7 do not significantly affect the distribution of the
ramonanin stereoisomers. As expected, the Naa and Xaa TSs
are the most favorable, presumably because both pairs of
phenyl groups (i.e., from diene and dienophile) occupy the
anti space with respect to the bond-forming zone, with the
former lying 3 kJmolÀ1 below the latter, in accordance with
Figure 1. Transition Structures Naa and Nss with bond lengths of the
newly formed bonds.
It seems surprising that neat samples of cis-7 readily
dimerize, as does cyclopentadiene (CPD), given that the
terminal methylene carbon atoms in 13 are calculated to be
3.139 ꢁ apart, compared to only 2.363 ꢁ in CPD.[20] The M06-
2X computed activation enthalpies and free energies for the
dimerization of CPD, 1,2-dimethylenecyclopentane, 3,4-
dimethylenetetrahydrofuran, and 13 are listed in Table 2.
As may be seen from Table 2, DH° for Diels–Alder
dimerization is approximately the same for all four reactants
and, in particular, neither the presence of phenyl groups nor
that of the ring oxygen has any significant effect on DH°
(compare entries 3 with 4 and 2 with 3). However, DG° for
the dimerization of 13 is about 10 kJmolÀ1 higher than in the
other three systems, for which similar values are obtained.
This free energy difference translates into a 50-fold decrease
in the Diels–Alder dimerization rate for 13, compared to the
other dienes listed in Table 2. The origin of this effect is
probably due to the phenyl groups in 13 experiencing a steeper
potential for their torsional motion about the bonds connect-
ing them to the tetrahydrofuran ring in the TS, compared to
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Table 2: DH° and DG° values (kJmolÀ1, 258C) for the Diels–Alder
Information System) on-line database, http://www.itis.gov.
Listed as endangered on the IUCN (International Union for
the Conservation of Nature) Red List. Retrieved [07 – 18 – 2014],
from http://www.iucnredlist.org.
dimerization of various dienes.[a]
Entry
1
Reactant
DH°
DG°
[7] K. J. Chavez, X. Feng, J. A. Flanders, E. Rodriguez, F. C.
Schroeder, J. Nat. Prod. 2011, 74, 1293 – 1297.
60.7
121.7
[8] For a discussion of the role of total synthesis in addressing the
problem of natural product supply, see J. D. Keasling, A.
Mendoza, P. S. Baran, Nature 2012, 492, 188 – 189.
[9] This lack of literature precedent perhaps explains why Schroeder
and co-workers described the key step in their proposed
2
3
64.2
59.8
125.0
122.2
biosynthesis as having
a “Diels – Alder-like mechanism”
(Scheme 1). The most closely related example of this type of
Diels – Alder reaction comes from Bloomquist and co-workers
who, in 1956, synthesized 1,2-dimethylenecyclopentane and
reported that attempts to distil the product at 978C resulted in
dimerization, see: A. T. Blomquist, J. Wolinsky, Y. C. Meinwald,
D. T. Longone, J. Am. Chem. Soc. 1956, 78, 6057 – 6063.
[10] For an excellent review on biosynthetic Diels – Alder reactions,
see: E. M. Stocking, R. M. Williams, Angew. Chem. Int. Ed. 2003,
42, 3078 – 3115; Angew. Chem. 2003, 115, 3186 – 3223.
[11] S. L. Drew, A. L. Lawrence, M. S. Sherburn, Angew. Chem. Int.
Ed. 2013, 52, 4221 – 4224; Angew. Chem. 2013, 125, 4315 – 4318.
[12] Relatively few examples of total syntheses containing proposed
biomimetic radical cation Diels–Alder reactions have been
reported, see Ref. [11] and: a) H. Cong, C. F. Becker, S. J. Elliot,
M. W. Grinstaff, J. A. Porco, J. Am. Chem. Soc. 2010, 132, 7514 –
7518; b) S. Lin, M. A. Ischay, C. G. Fry, T. P. Yoon, J. Am. Chem.
Soc. 2011, 133, 19350 – 19353; c) H. N. Lim, K. A. Parker, Org.
Lett. 2013, 15, 398 – 401; d) C. Qi, H. Cong, K. J. Cahill, P. Mꢂller,
R. P. Johnson, J. A. Porco, Angew. Chem. Int. Ed. 2013, 52, 8345 –
8348; Angew. Chem. 2013, 125, 8503 – 8506; e) H. N. Lim, K. A.
Parker, J. Org. Chem. 2014, 79, 919 – 926.
4
58.0
132.2
[a] M06-2X/6-31G(d)-[PCM=THf]//M06-2X/6-31G(d) activation ener-
gies from the lowest energy (endo) path.
the reactant. In conclusion, these calculations support the
notion of a concerted cycloaddition event, both in the
synthesis and biogenesis of the ramonanin natural products.
In summary, a seven-step total synthesis of the ramonanin
natural products has been achieved. An investigation of the
chemistry of Schroeder’s proposed biosynthetic pathway has
pinpointed the most likely origin of these fascinating struc-
tures. The natural products have been shown to be racemates.
Our experimental results demonstrate that lignan 7 is
predisposed toward thermal Diels–Alder dimerization, and
our computational findings predict this behavior more widely
in the 1,2-dimethylene cyclopentane series. It remains unclear
whether this predisposed reactivity is being harnessed in
nature constructively, or is generating products that are
artifacts of isolation.
[13] For our previous biomimetic studies on dimeric natural products,
see Ref. [11] and: a) P. D. Brown, A. C. Willis, M. S. Sherburn,
A. L. Lawrence, Angew. Chem. Int. Ed. 2013, 52, 13273 – 13275;
Angew. Chem. 2013, 125, 13515 – 13517; b) P. D. Brown, A. C.
Willis, M. S. Sherburn, A. L. Lawrence, Org. Lett. 2012, 14,
4537 – 4539.
Received: October 6, 2014
Published online: && &&, &&&&
[14] Selected examples: a) A. Kinoshita, N. Sakakibara, M. Mori, J.
Am. Chem. Soc. 1997, 119, 12388 – 12389; b) K. Tonogaki, M.
Mori, Tetrahedron Lett. 2002, 43, 2235 – 2238; c) M. Mori, K.
Tonogaki, N. Nishiguchi, J. Org. Chem. 2002, 67, 224 – 226.
[15] The half-lives of both diastereomers of lignan 7 were determined
to be approximately 2 days, for mixtures of diastereomers
dissolved in a minimum of DMF (14.6m) at 258C; see the
Supporting Information for details.
[16] The cis and trans diastereomers of compound 12 could be
separated by preparative HPLC and then used to prepare pure
samples of cis-7 and trans-7, see the Supporting Information for
details.
[17] The reaction was halted before completion to avoid the
formation of decomposition products. Attempts to bring about
a RCDA reaction using aminium radical catalysis (D. A. Bell-
ville, D. D. Wirth, N. L. Bauld, J. Am. Chem. Soc. 1981, 103, 718 –
720), or photoredox catalysis (Ref. [12b]), were met with failure.
[18] An authentic sample of ramonanin B was not available.
[19] Full details of these calculations are given in the Supporting
Information.
Keywords: biomimetic synthesis · Diels–Alder reactions ·
.
enyne metathesis · lignans · natural products
[1] a) R. S. Munger, J. Hist. Med. Allied Sci. 1949, IV, 196 – 229;
b) J. F. Morton, Atlas of Medicinal Plants of Middle America:
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[2] M. K. Nobles, Can. J. Bot. 1958, 36, 91 – 99.
[3] D. C. Rockey, N. Engl. J. Med. 1999, 341, 38 – 46.
[4] W. Autenrieth, Laboratory manual for the detection of poisons
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Philadelphia, 1915, pp. 21 – 22.
[5] The structure of guaiacum blue (2) in Scheme 1a is that shown in
the following publication, but it should be noted that this
compound has never been fully characterized, see: J. F. Kra-
tochvil, R. H. Burris, M. K. Seikel, J. M. Harkin, Phytochemistry
1971, 10, 2529 – 2531.
[20] The fast Diels – Alder dimerization of cyclopentadiene has been
ascribed to its short C1 – C4 distance, see: R. Sustmann, M.
Bçhm, J. Sauer, Chem. Ber. 1979, 112, 883 – 889.
[6] “Guaiacum officinale L.” Taxonomic Serial No.: 897104
Retrieved [07 – 18 – 2014], from the ITIS (Integrated Taxonomic
4
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Angewandte
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Communications
Total Synthesis
R. S. Harvey, E. G. Mackay, L. Roger,
M. N. Paddon-Row,* M. S. Sherburn,*
A. L. Lawrence*
&&&& — &&&&
Total Synthesis of Ramonanins A–D
Dimers of dimers: The first total syn-
thesis of the ramonanin family of natural
products has been achieved in short
order. These natural phenylpropanoid
tetramers were assembled in seven steps
from the starting materials vanillin, eth-
ylene, and the ethynyl Grignard reagent.
Computational studies shed light on
a surprisingly facile Diels–Alder dimeri-
zation.
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