A short access to the skeleton of elisabethin a and formal syntheses of elisapterosin B and colombiasin A

Article abstract of DOI:10.1021/ol501998y

A short stereoselective synthesis of the Elisabethin A skeleton 4 is described, which opens a formal access to the diterpenes Elisapterosin B and Colombiasin A as well. Key reactions were an intermolecular endo-selective Diels-Alder reaction to generate t

Full text of DOI:10.1021/ol501998y

Letter
pubs.acs.org/OrgLett
A Short Access to the Skeleton of Elisabethin A and Formal
Syntheses of Elisapterosin B and Colombiasin A
Johannes Preindl, Christian Leitner, Simon Baldauf, and Johann Mulzer*
University of Vienna, Institute of Organic Chemistry, Waehringer Strasse 38, 1090 Wien, Austria
*
S Supporting Information
ABSTRACT: A short stereoselective synthesis of the Elisabethin A skeleton 4 is described, which opens a formal access to the
diterpenes Elisapterosin B and Colombiasin A as well. Key reactions were an intermolecular endo-selective Diels−Alder reaction
to generate the decalin part of the molecule, a chemo- and diastereoselective allylation of an aldehyde with allylzinc, a palladium
ene annulation of the cyclopentane ring, and a novel sulfonium ylide induced fragmentation of a polycyclic ketone. Additional
insights have been gained for the crucial epimerization at C-2.
n 1998, the Rodriguez group reported the isolation and
characterization of three diterpenoids with unusual struc-
them quaternary. It is no wonder, then, that this target has also
attracted significant interest among synthetic chemists. About
3
I
tures and interesting biological activities from the West Indian
sea whip Pseudopterogorgia elisabethae, collected in deep waters
near San Andreas Island (Colombia). Appropriately, these
compounds were called Elisabethin A (1), Elisapterosin B (2),
and Colombiasin A (3) (Figure 1), and it has been postulated
10 years ago the Rawal group and our group published4
approaches to 1 via intramolecular Diels−Alder addition,
which due to some stereochemical assignments have met with
5
criticism from outside. This prompted us to test a different
strategy, now based on intermolecular Diels−Alder cyclo-
1
6
that they are biogenetically interconnected via Elisabethin A.
addition. Our retrosynthetic plan of 1 (Scheme 1) was so
designed to build up the six stereocenters step by step, which
should allow us to assign the configuration of every single
carbon atom individually. The decalin system was to be
constructed first to install the crucial quaternary center, before
Scheme 1. Retrosynthetic Plan of 1
Figure 1. Structures of Elisabethin A and two related diterpenes.
2
and 3 have been frequently visited synthetic targets, due to
2
their demanding architecture and interesting biological profile.
Most of these syntheses have utilized an intermolecular Diels−
Alder addition to construct a decalin type intermediate first,
which was then converted either into 3 via an intramolecular
2
b−d,f,g
Diels−Alder reaction
or into 2 via a [5 + 2]-
As an alternative, Harrowven et al. have
prepared a bicyclic intermediate via an annulation to
2
d,e,g
cycloaddition.
2
e
dihydrocarvone, and Jacobsen et al. have converted 3 directly
into 2. The Rawal group reported the asymmetric synthesis of
2
f
2
via an intramolecular Diels−Alder reaction with subsequent
2h
oxidation. Similarly fascinating is the tricyclo[7.4.0.01,5]-
tridecane ring system of 1, which features a fully substituted
enedione moiety and six contiguous stereogenic centers, one of
Received: July 9, 2014
Published: August 4, 2014
©
2014 American Chemical Society
4276
dx.doi.org/10.1021/ol501998y | Org. Lett. 2014, 16, 4276−4279

Organic Letters
Letter
annulating the cyclopentane ring via a Heck-type metallo-ene
cyclization. A particular challenge lies in the enolization/
annulation of the cyclopentane ring we utilized a palladium ene
cyclization which was developed by Oppolzer et al. in the late
7
13
epimerization of C-2, which has been a problem in the Rawal
1980s but has received little attention in total synthesis so far.
Gratifyingly, heating of compounds 18a,b with tetrakis-
(triphenylphosphine)palladium in glacial acetic acid afforded
the envisaged tricycles 19a,b in excellent yield. Hydrogenation
with palladium on charcoal gave intermediates 20a,b with the
desired configuration at C-7, which was verified by NOE
experiments. Although the hydrogenation of the exocyclic
double bond in 19a,b seems to occur from the more hindered,
concave site of the molecule, MM2 energy minimization of a
4
b
synthesis. The last stage of the synthesis should deal with the
isobutenyl side chain at C-9.
8
Our synthesis started with the known compounds 8 and 9.
Treatment of this mixture with silver(I) oxide led to the Diels−
6
Alder adduct 10 as a pure diastereomer. In view of the
presence of two additional carbonyl groups, we expected
regiomeric problems for the allylation of the aldehyde. In fact,
standard Grignard conditions resulted in the formation of a
complex, inseparable product mixture. An iodine-catalyzed
Sakurai reaction, described in the literature as a selective
3
D model of 19a showed that the carbonyl at C-14 adopts an
axial position which directs the hydrogenation to the opposite
face (Scheme 3).
9
allylation of aldehydes, afforded a complex product mixture as
well. Allylation with tributylallylstannane, as well as Brown or
10
Barbier type allylations, also failed. After that the Nozaki−
Scheme 3. Synthesis of Tricyclic Intermediate 20
11
Hiyama−Kishi (NHK) allylation was tried. With an excess of
CrCl in DMF, however, tricycle 11 was the only product in
2
quantitative yield, and none of the desired allyl adduct had been
formed. This result nicely agrees with our earlier mechanistic
studies of the NHK reaction in which ketyl radical anion
12
intermediates such as 12 and 13 have been postulated
Scheme 2). Obviously, this pathway is much faster than a
(
Scheme 2. Synthesis of Decalin 10 and the Formation of 11
under NHK Conditions
competing formation of the chromium allyl species and its
addition to the aldehyde. The crystal structure of 11 confirmed
the relative configuration of adduct 10 and, hence, the endo
selectivity of the Diels−Alder reaction as well.
After that, we replaced the TBS group with the more labile
10c
TES ether and switched from NHK to allyzinc allylation.
Hence, diene 15 was prepared from aldehyde 14 as an E/Z
mixture containing 30−35% of the required (E/E)-diene. In
situ treatment of aldehyde 8 with an excess of the diene mixture
and silver(I) oxide led to diastereomerically pure Diels−Alder
adduct 16. Transmetalation of allylmagnesium chloride with
Having thus established the relative configurations of five
stereogenic centers in 20a,b properly, we ventured on the
elaboration of the side chain at C-9 (Scheme 4). Removal of
the acetate by standard hydrolysis led to extensive decom-
position. In the end, we took recourse to a global reduction of
all carbonyls in 20a,b with lithium aluminum hydride. A
mixture of epimeric alcohols was formed which, without
separation and purification, was reoxidized with IBX to give
ketone 4 as a single product. Transformation of the keto moiety
of 4 into the corresponding enol triflate 21 worked smoothly.
All attempts to introduce the isobutenyl group by direct CC
coupling failed. In the end, carbonylation of the triflate led to
ZnCl and addition of the resulting zinc organyl to 16 provided
2
an inconsequential mixture of the two diastereomeric
homoallylic alcohols 17a,b in a ratio of 4:1 and 95% yield.
To facilitate NMR analysis, the epimers were separated and
acetylated with acetic anhydride. cis−trans epimerization at C-2
with DBU, removal of the TES ether, and acetylation afforded
intermediates 18a,b in almost quantitative yield. For the
4
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Organic Letters
Letter
a
Scheme 4. Synthesis of Elisabethin A Derivatives 22−24
Scheme 6. Retro-Claisen Cleavage of Ketone 4 and Formal
Synthesis of Diterpenes 2 and 3
a
concomitant aromatization and considerable strain release. A
number of bases were tried in vain, until we found that
trimethylsulfonium methylide induced a clean conversion of 4
into lactone 28. Presumably, a regioselective attack of
trimethylsulfonium methylide onto ketone 4 affords alkoxide
26, which undergoes a retro-Claisen reaction to form
intermediate 27. Attack of the phenolate at the α-sulfonium
ketone releases trimethylsulfonium methylide and generates the
seven-membered lactone 28. LAH reduction directly afforded
quinone 29 after oxidative workup (Scheme 6). TIPS
protection of the primary alcohol led to 30, whose spectral
data matched the corresponding intermediate in Rychnovsky’s
Abbreviations: IBX, 2-iodobenzoic acid; Comins’ reagent, 2-[N,N-
bis(trifluoromethanesulfonyl)amino]-5-chloropyridine; Crabtree’s cat-
alyst, (SP-4)-[tris(cyclohexyl)phosphane][(1,2-η:5,6-η)-cycloocta-1,5-
diene]pyridineiridium(1+) hexafluoridophosphate.
ester 22; however, this occurred under complete epimerization
14
of H-2 from the axial to an equatorial position. Interestingly,
the carbonylation of 21 to aldehyde 23 proceeded without
epimerization, obviously due to the absence of methanol in the
reaction mixture. Similarly, when acetate 20a was treated with
HCl/methanol, the stable enol 25 was formed and the carbonyl
moiety was not restored (Scheme 5). These observations
2d
synthesis of Elisapterosin B (2) and Colombiasin A (3). This
result not only constituted a diastereocontrolled access to these
compounds but also confirmed the correct relative config-
urations of C-3, C-6, and C-7 in intermediate 20.
Scheme 5. Enolization of C-2
In conclusion, we have presented a rapid and stereo-
controlled access to the Elisabethin A skeleton (eight steps
(
34%) to ketone 4) and formal syntheses of Elisapteroside B
and Colombiasin A as well. Key reactions were an
intermolecular endo-selective Diels−Alder reaction to generate
the decalin part of the molecule, a base catalyzed trans−cis
epimerization at C-2, a chemoselective aldehyde allylation with
allylzinc, a palladium ene annulation of the cyclopentane ring,
and a sulfonium ylide induced fragmentation to generate a
tricyclic phenolic lactone.
indicate that the thermodynamically favored trans decalin ring
fusion in the bicyclic compounds 17 and 18 has been
destabilized by the spiroannulation of the cyclopentane,
which means that naturally occurring Elisabethin A most likely
represents the thermodynamically more labile C-2 epimer.
Next, we tried to reduce the α,β-unsaturated double bond.
Aldehyde 23 was inert, whereas ester 22 was hydrogenated to
ASSOCIATED CONTENT
Supporting Information
■
*
S
15
24 with Crabtree’s catalyst and dihydrogen. Unfortunately,
Text, figures, and a CIF file giving all synthetic procedures and
NMR data for the compounds prepared in this paper and
crystallographic data for compound 11. This material is
available free of charge via the Internet at http://pubs.acs.org.
ester 24 proved totally inert toward any kind of C elongation,
so that Elisabethin A could not be reached. Instead, we turned
2
to the synthesis of the diterpenes 2 and 3 (Scheme 6). It
occurred to us that, due to the rigid geometry of the polycyclic
skeleton, the C-1−C-9 bond in ketone 4 adopts a perpendicular
position with respect to the cyclohexenedione ring.
AUTHOR INFORMATION
Corresponding Author
■
Stereoelectronically this should facilitate a Grob−Eschen-
16
moser fragmentation like retro-Claisen cleavage, promoted by
*E-mail for J.M.: johann.mulzer@univie.ac.at.
4
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Organic Letters
Letter
Notes
(10) Reviews: (a) Ramachandran, P. D.; Gagare, D. R.; Nicponski, P.
V. Allylborons. In Comprehensive Organic Synthesis II; Knochel, P.,
Molander, G. A., Eds.; Elsevier: Amsterdam, 2014; Vol. 2 (Mikami, K.,
Ed.), pp 1−71. (b) Allylsilanes and allylstannanes: Ramachandran, P.
D.; Nicponski, P. V.; Gagare, D. R. Allylsilanes, Allylstannanes, and
Related Compounds. In Comprehensive Organic Synthesis II; Knochel,
P., Molander, G. A., Eds.; Elsevier: Amsterdam, 2014; Vol. 2 (Mikami,
K., Ed.), pp 72−147. (c) Allylzinc: Ender, E. Zinc Reagents in Organic
Synthesis; CRC Press: Boca Raton, FL, 1996.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Austrian FWF (Fonds zur Fo
̈
rderung der Wissenschaften)
is thanked for financial support (project P22180-N19). We are
grateful to the following colleagues (all at the University of
Vienna): Hans Peter Kaehlig, Lothar Brecker, and Susanne
Felsinger, who recorded important NMR spectra and helped us
with their interpretation; Alexander Roller and Vladimir Arion,
who provided us with the crystal structure of compound 11.
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1
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