An Intramolecular Cycloaddition Approach to the Kauranoid Family of Diterpene Metabolites

Article abstract of DOI:10.1021/acs.orglett.8b03810

Synthetic studies toward the ent-kauranoid family of diterpene natural products are reported. An intramolecular (4 + 3) cycloaddition allows the direct elaboration of diverse natural product frameworks, encompassing a challenging bicyclo[3.2.1]octane core. The established routes comprise only a few synthetic operations (3-5 steps), transforming a range of simple starting materials into the tetracyclic scaffolds that are commonly found in many ent-kaurene metabolites.

Full text of DOI:10.1021/acs.orglett.8b03810

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
An Intramolecular Cycloaddition Approach to the Kauranoid Family
of Diterpene Metabolites
Brenda Callebaut,† Jan Hullaert,† Kristof Van Hecke,‡ and Johan M. Winne*,†
†Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281 S4, 9000 Gent, Belgium
‡XStruct, Department of Chemistry, Ghent University, Krijgslaan 281 S3, 9000 Ghent, Belgium
S
* Supporting Information
ABSTRACT: Synthetic studies toward the ent-kauranoid family of diterpene natural products are reported. An intramolecular
(4 + 3) cycloaddition allows the direct elaboration of diverse natural product frameworks, encompassing a challenging
bicyclo[3.2.1]octane core. The established routes comprise only a few synthetic operations (3−5 steps), transforming a range of
simple starting materials into the tetracyclic scaffolds that are commonly found in many ent-kaurene metabolites.
ne of the most diverse and, at the same time, structurally
intriguing subfamily of plant diterpenes is formed by the
natural product inspired synthesis, the kauranoid skeleton can
also be identified as a highly privileged scaffold.5
O
ent-kauranes (Figure 1).1,2 The parent geranylgeranyl pyro-
To date, general and concise synthetic approaches to the
intruiging 6:6:6:5 ring system encompassing the [3.2.1]bicyclic
core are still rare.3,4 Snider’s racemic 18-step isosteviol
synthesis stands out in this regard (Scheme 1a),6 which
elaborates the ent-beyerane framework in just 12 steps via an
impressive free radical polyene cyclization, completing
isosteviol in 18 linear steps. The beyerane scaffold found in
isosteviol shares its overall connectivity with the ent-kaurane
core, but it is, in fact, a regioisomeric and stereoisomeric
skeleton which can interconvert via a rearrangement to the
more commonly found ent-kaurane skeleton (C-12 migrates
between C-16 and C-13; see Figure 1 ). Baran more recently
reported the shortest (racemic) synthesis of steviol,7
completing the kaurane core in just 12 steps as an “overbred”
intermediate (Scheme 1b), with an additional C-12 to C-16
bond that is cleaved during the final stages of the synthesis. A
similar strategy for the kaurane and beyerane frameworks was
developed by Abad in 2006,8 first establishing a C-12 to C-16
reconnected core in just 9 steps, using an intramolecular
cyclopropanation approach. In 1986, De Clercq reported the
shortest racemic total synthesis of a gibberellin plant
hormone,9 comprising 16 linear steps and taking only 8 steps
to elaborate the 6:5:6:5 tetracyclic core via an intramolecular
Diels−Alder reaction with a furan diene (Scheme 1d).
Gibberellic acids are ent-kaurene metabolites that have
undergone a C-8 migration from C-7 to C-6, with conservation
of the challenging bicyclo[3.2.1]octane core (Figure 1). Very
recently, Njardarson reported another concise racemic entry to
Figure 1. Common tetracyclic scaffolds found in ent-kaurene
metabolites and three representative natural products that have
been classical targets for total synthesis.
phosphate diterpenoid is directly transformed to ent-kaurene
via two cyclase enzymes, each catalyzing a bicyclization event,
yielding a remarkable tetracyclic framework, which, in itself, is
the direct precursor of a huge family of skeletally complex
natural products, also including the well-known gibberellin
plant hormones. The chemical biodiversity and complexity
found in ent-kaurene metabolites actually approaches that
found in steroids, since over a thousand kaurene metabolites
are known, which continue to attract considerable interest
from both a synthetic and a biological point of view.3,4
Drawing on the arguments of biology-oriented synthesis, or
Received: November 28, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03810
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Letter
Scheme 1. Concise Synthetic Approaches for Kauranoids
Scheme 2. Synthesis of Gibberellane Scaffolds 7a and 7b
the gibberellane core requiring only 9 steps,10 using an
intramolecular Diels−Alder reaction to establish a [2.2.2]-
bicycle which can be rearranged to a [3.2.1]bicyclic system via
a 1,2- (or 1,5-) carbon shift (Scheme 1d). We now report our
own synthetic studies in this field, aiming at a direct
elaboration of the [3.2.1]bicyclic system via an intramolecular
(4 + 3) cycloaddition (Schemes 1e and 2).11 The results
reported herein establish a very short and conceptually
straightforward entry into kaurane-type scaffolds.
We set out to synthesize kaurane-type scaffolds as part of a
program to further establish the utility of furan-mediated allyl
cation (4 + 3) cycloadditions (Scheme 1e), a remarkably
efficient synthetic method for seven-membered ring systems
that was first observed by Pattenden and Winne in 2009,12 and
has since been developed by our group and others in recent
years.13,14 The methodology has been used to elaborate a
bicyclo[3.2.1]octane system in previous studies aimed at a
gelsemine substructure by Zhang, Li, and co-workers,14 using
an intermolecular approach, and also in an intramolecular
version in a synthesis of the zizaene sesquiterpene scaffold by
Laplace and Winne.15 These results raise expectations
concerning the viability of such an approach for the important
and ubiquitous kaurane-type scaffolds (cf.n Scheme 1e).
Thus, we identified bromo-aldehyde 1 as a suitable starting
material (Scheme 2), which can be obtained in a single step
from the corresponding commercial bromonitrile.16 Addition
of a lithiated furan moiety, followed by substitution of the
unreacted primary bromide with the cyclopentadienyl anion
would provide the intramolecular cycloaddition precursor 2 in
a very small number of synthetic operations. In fact, best
results were obtained using a one-pot procedure to perform the
addition and substitution reactions on the bis-electrophile 1.
Not unexpectedly, treatment of 1 with lithiated 2-methyl furan,
followed by workup, gave the cyclic ether 3 as the major
reaction product. However, by making sure the nucleophilic
oxyanion is captured in situ by trimethyl silyl chloride, and
then adding an excess of cyclopentadienyl sodium, a very clean
three-component assembly of the silyl ether 2 was obtained,
without detectable formation of the tetrahydrofuran-type
product 3.
With precursor 2 in hand, our investigation next involved
the generation of the furfuryl cation derived from 2 as a
suitable dienophile for the pendant cyclopentadiene moiety
(cf. Scheme 1e). Although the expected gibberellane-type
cycloadduct 4 was formed under our three standard reaction
conditions (see Table 1, entries 1−3),13a,15,17 it was invariably
isolated together with a complex mixture of isomeric products
which could be assigned the overall tetracylic structure 5.
These isomers most likely result from the “incorrect” Cp
Table 1. Intramolecular Annulation Studies of Silyl Ether 2
entry
reaction conditions (2 in CH2Cl2)
yield (%)
ratio 4:5
1
2
3
4
0.8 equiv FeCl3·6H2O, 0 °C, 0.75 h
2.0 equiv CF3CO2H, −10 °C, 1.5 h
0.2 equiv Ga(OTf)3, rt, 1.25 h
16
23
50
98
1:3
4:5
1:1
1:1
cf. entry 3, performed on gram scale
B
DOI: 10.1021/acs.orglett.8b03810
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Letter
isomer wherein the furfuryl cation is attacked from a different
Cp position, resulting in monocyclized products (see the
Supporting Information). Using Wu’s conditions with gallium-
(III) triflate,18 best results were obtained on a small scale
screening (Table 1, entry 3), and the observed product ratio
indeed closely resembles that of the interconverting Cp
positional diene isomers of the starting material. Upon scale-
up to gram scale, without intermediate purification of the labile
silyl ether 2, we were pleased to find that these conditions gave
an almost quantitative conversion to 4 and 5 (Table 1, entry
4). A hydroboration of the alkene moieties allowed a
straightforward separation of the monohydroxyl compounds
6a and 6b derived from 2, and the dihydroxyl compounds
derived from 5. Starting from four grams of 1, more than one
gram of 6a and 6b were isolated. Final Swern oxidation gave
the separable regio-isomeric ketones 7a and 7b, both obtained
in a synthetically useful overall yield from bromoaldehyde 1.
Furthermore, these crystalline derivatives provided a con-
clusive structural and stereochemical assignment of the natural
gibberellane/gibbane framework via single-crystal X-ray
diffraction analysis. The relatively low yields for the key
cycloaddition are counterbalanced by the small number of
steps and rapid increase in molecular weight and complexity.
Encouraged by the remarkable brevity and level of
stereocontrol in the assembly of the tetracyclic core shared
by gibberellane plant hormones (viz 1 → 4, 6, 7), we next
explored the scope of this attractive sequence using a number
of readily available bromo-aldehydes (Figure 2). The
product-derived screening collections.19 Finally, the homolo-
gous bromo-aldehyde 11 gave access to the ring-expanded
scaffold 15, again obtained as a single diastereomer.
Having established the feasibility of an intramolecular (4 +
3) approach for gibberellane-type scaffolds, we next turned to
an investigation of the “parent” kauranoid scaffolds with a six-
membered B-ring, with its steroid-like trans-fusion to a
saturated A-ring (Figure 1). For this purpose, we identified
bromoaldehyde 17 as a very interesting starting material
(Scheme 3). This unsaturated aldehyde can be prepared in two
Scheme 3. Synthesis of the Kauranoid Scaffolds 20 and 21
steps from the commercial bromoalkene 16 via a well-
established regioselective and stereoselective allylic oxidation
protocol.20 Before exploiting the double electrophilic nature of
this intermediate in the one-pot bisfunctionalization protocol
described above for bromoaldehyde 1, we envisaged the use of
the electron-poor alkene as a good synthetic handle to install
the trans-substituted six-membered A-ring found in kaurane-
derived diterpenoids, via a straightforward Diels−Alder
reaction. Using simple isoprene and a Lewis acid catalyst the
resulting bromoaldehyde 18 was cleanly afforded as a single
regio-isomer and stereoisomer, which was then subjected to
the one-pot procedure to give the intramolecular cycloaddition
precursor 19 in 66% yield. This intermediate was obtained as a
mixture of inconsequential C-9 diastereomers, and its NMR
analysis was further complicated by the presence of the
expected positional diene isomers of the Cp moiety. Never-
theless, when silyl ether 19 was subjected to allyl cation-
generating conditions, only two reaction products were
obtained, shown to be stereoisomers 20 and 21, both
encompassing the expected kaurane-type scaffold. The major
isomer 20 can be separated by flash chromatography and
readily crystallized in pure form, allowing the unambiguous
assignment of the relative stereochemistry, corresponding to
that found in the beyerane-series of ent-kaurene metabolites.
Intriguingly, the diastereoselectivity, with respect to the BCD-
ring fusion, thus seems to be almost completely inverted, with
respect to the A-ring aromatic scaffolds 4 and 12−15 (vide
Figure 2. Additional gibberellane-type scaffolds 12−15 (obtained in
racemic form) from simple bromo-aldehyde starting materials 8−11,
and a comparison to the structure found in natural gibberic acid.
“unbiased” substrate 4-bromopentaldehyde 8 gave the
expected partial kauranoid scaffold 12 with the same level of
overall efficiency and stereoselectivity. Similarly, the more
substituted bromo-aldehydes 9 and 10 gave very similar results
to those obtained with bromoaldehyde 1. The cycloadduct 14
was even obtained with good stereocontrol of the additionally
introduced stereocenter, with the major relative stereo-
chemistry corresponding to that found in the closely related
naturally derived gibberic acid, which recently attracted
significant interest as a scaffold to develop focused natural
C
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supra). The minor diastereomer 21 could be tentatively
assigned the natural kaurane relative stereochemistry, also
found in norkauranoid 15, based on 2D NMR analysis
performed on an enriched sample (see the Supporting
Information).
synthesis of precursor 23 from bromoaldehyde 18 via the one-
pot procedure was severely hampered by the lower reactivity of
the lithiated sulfur heterocycle toward the aldehyde function,
resulting in an unavoidable competition with the formation of
cyclic ether 24, and necessitating an intermediate workup and
purification. Nevertheless, sufficient amounts of the required
cycloaddition precursor 23 could thus be prepared to allow a
study of its intramolecular annulation. This proceeded in only
modest yield, returning the expected beyerane scaffold 25 as
the major reaction product. However, a range of several minor
inseparable annulation products 26 were formed and
coisolated, which were tentatively assigned a fused 6:6:5:5
After exploring our three standard reaction conditions for
the annulation of 19 and some optimization (cf. Table 1; see
the Supporting Information), the best results were now
obtained with trifluoroacetic acid (40% isolated yield), using
prolonged reaction times at 0 °C. Interestingly, we were unable
to observe monocyclized side products under any of these
conditions, or even isolate any other side products
corresponding to the incorrect Cp-regioisomer of 19. This
may reflect the significant increase in distance between C-9
and C-15, which could favor intermolecular reactions over
intramolecular ones in the case of the Cp-regio-isomeric
furfuryl cation intermediates, ultimately resulting in an
intractable mixture of oligomers as easily separated side
products. The major isomer is readily separated by flash
chromatography, typically providing 10%−20% isolated yield
of the pure diastereomer 20 (5%−10% overall from 17).
With the pure furanobeyerane 20 in hand, we also briefly
explored the decoration and functionalization of this scaffold
into more natural product-like motifs (Scheme 4). Simple
1
ring system, based on the H NMR spectral similarity to
known hydropentalene ring systems.22 These minor side
products appear to correspond to the product of a competitive
allyl cation (3 + 2) cycloaddition. Indeed, in previous studies
on this heterocycle, we found that (3 + 2) cycloaddition
pathways can also occur.13a,21
In summary, although the inherent diene isomerism of
cyclopentadienyl units clearly limits the efficiency of our
reported strategy, we have nevertheless achieved a remarkably
short, and also scalable entry into the wide class of kaurane
metabolite-type scaffolds. We have demonstrated six different
sequences starting from different bromo-aldehydes with low
but consistent overall yields, offering good to excellent
stereocontrol, with regard to both of the naturally occurring
beyerane and the kaurane/gibbane bicyclo[3.2.1]octane
relative configurations. Although the use of this approach as
a “late stage” transformation in a multistep synthesis of natural
products may be limited, it should offer good opportunities for
the rapid exploration of kauranoid chemical space via the
generation of diversely substituted scaffolds derived from
exceedingly simple building blocks in just a few synthetic
operations. Work along these lines is currently underway and
will be reported in due course.
Scheme 4. Additional Derivatization and Cycloaddition
Experiments To Access Advanced Intermediates towards
Kauranoid Natural Products
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03810.
Experimental procedures; spectral and X-ray crystallog-
raphy data (PDF)
Accession Codes
CCDC 1861785−1861787 contain the supplementary crys-
tallographic data for compounds 20, 7b and 7a. These data can
be obtained free of charge via www.ccdc.cam.ac.uk/data_
request/cif, or by emailing data_ request@ccdc.cam.ac.uk, or
by contacting The Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK; fax: + 44 1223
336033.
treatment with mCPBA gave a regioselective and stereo-
selective olefin epoxidation with competitive oxidative cleavage
of the furan ring, releasing the core tetracyclic beyerane 22 as
the major isolated reaction product.
Finally, inspired by recent research results from our group
involving allyl cation-type cycloadditions derived from
dihydrodithiin-substituted alcohols,13a,21 we also briefly ex-
plored this heterocycle type. One advantage of this cyclo-
addition-mediating sulfur heterocycle is the fact that it can be
removed via hydrodesulfurization, resulting in the product of a
formal (4 + 3) cycloaddition of a naked allyl cation. The
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: johan.winne@ugent.be.
ORCID
Johan M. Winne: 0000-0002-9015-4497
D
DOI: 10.1021/acs.orglett.8b03810
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Letter
(9) Grootaert, W. M.; De Clercq, P. J. A novel expeditious entry into
gibberellins. The total synthesis of ( )-GA5. Tetrahedron Lett. 1986,
27, 1731.
(10) Smith, B. R.; Njardarson, J. T. [2.2.2]-to [3.2.1]-Bicycle
Skeletal Rearrangement Approach to the Gibberellin Family of
Natural Products. Org. Lett. 2018, 20, 2993−2996.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
(11) For related examples in synthesis and reviews, see:
(a) Hoffmann, H. M. R.; Eggert, U.; Gibbels, U.; Giesel, K.; Koch,
O.; Lies, R.; Rabe, J. Nucleophilic Organosilicon Intermediates
Turned Electrophilic:(Trimethylsilyl) methyl, Trimethylsilyloxy and
also 2-Tetrahydropyranyloxy as Terminators of Cycloadditions of
Allyl Cations. A Short Route to Dehydrozizaenes (6-Methylene-
tricyclo [6.2. 1.01, 5]-undec-9, 10-enes) and Related Tricycles and
[3.2. 1]-Bicycles. Tetrahedron 1988, 44, 3899. (b) Jones, D. E.;
Harmata, M. Application of the [4 + 3] Cycloaddition Reaction to the
Synthesis of Natural Products. In Methods and Applications of
Cycloaddition Reactions in Organic Syntheses; Nishiwaki, N., Ed.;
Wiley, 2014. (c) Harmata, M. The (4+ 3)-cycloaddition reaction:
simple allylic cations as dienophiles. Chem. Commun. 2010, 46, 8886.
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34, 595.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Jan Goeman (Ghent University) for help with MS
analyses, and Tim Courtin and Dieter Buyst of the NMR
Expertise Centre (Ghent University) for help in NMR
experiments. B.C. thanks FWO Vlaanderen for a scholarship.
J.H. thanks IWT/VLAIO Hermes Fonds for a scholarship.
K.V.H. thanks the Hercules Foundation (project AUGE/11/
029 “3D-SPACE: 3D Structural Platform Aiming for Chemical
Excellence”) and the Special Research Fund (BOF)−UGent
(Project No. 01N03217) for funding. J.W. thanks the Special
Research Fund (BOF)−UGent (Project No. STA043-17).
(12) Pattenden, G.; Winne, J. M. An intramolecular [4+ 3]-
cycloaddition approach to rameswaralide inspired by biosynthesis
speculation. Tetrahedron Lett. 2009, 50, 7310.
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