Total synthesis of (-)-anominine

Article abstract of DOI:10.1021/ja101994q

The first total synthesis of anominine has been achieved, and the absolute configuration of the product has been determined. The key features include the development of a new, highly efficient organocatalyzed method for the asymmetric synthesis of Wieland-Miescher ketone building blocks, an unusual selenoxide [2,3]-sigmatropic rearrangement, and a ZrCl⁴-catalyzed indole coupling as well as several chemoselective transformations controlled by the structurally congested nature of the bicyclic core.

Full text of DOI:10.1021/ja101994q

Published on Web 04/12/2010
Total Synthesis of (-)-Anominine
Ben Bradshaw,* Gorka Etxebarria-Jard´ı, and Josep Bonjoch*
Laboratori de Qu´ımica Orga`nica, Facultat de Farma`cia, UniVersitat de Barcelona, AV. Joan XXIII s/n,
08028 Barcelona, Spain
Received March 9, 2010; E-mail: benbradshaw@ub.edu; josep.bonjoch@ub.edu
Scheme 1. Organocatalyzed Asymmetric Synthesis of 3
Many fungi produce specially adapted morphological structures
called sclerotia that are critical to the long-term survival and
propagation of the species. A systematic study of the sclerotia of
Aspergillus spp. by Gloer’s group several years ago led to the
isolation of many unique, biologically active secondary metabolites.1
Among these, our interests have focused on diterpenoids with novel
ring structures characterized by two quaternary carbons at the
decalin ring junction2 and up to six contiguous stereocenters all
arranged in a cis configuration (Figure 1). To date, none of these
highly congested and structurally challenging diterpenoids have
been synthesized,3 nor have their absolute configurations been
established.
the subsequent conjugated addition reaction to give 4 and set up
the second quaternary center.
A second relay procedure introduced the double bond at C11 by
chemoselective protection of the less hindered carbonyl group of
4 followed by a Wittig methylenation and acid quench of the
initially formed acetal (Scheme 2). Oxidation of ketone 5 with IBX
in the presence of TsOH8 formed the endocyclic enone 6, which
not only ensured the regioselectivity for the next alkylation step
but also provided the necessary functionality for the rearrangement
required to install the oxygen atom at C19. With the contiguous
quaternary carbons in place, we then found that many attempted
transformations failed, particularly when the reactive site was
adjacent to one of the quaternary centers. For example, alkylation
to introduce the C28 methyl with LiHMDS/MeI/HMPA was
precluded by the predominance of O-alkylation, and plans to move
the oxygen from C17 to C19 by a Wharton transposition were also
thwarted by the unreactive nature of the internal double bond toward
epoxidation. However, reaction of the lithium enolate of 6 with
Eschenmoser’s salt followed by m-CPBA oxidation of the resulting
Figure 1. Representative diterpenoids with a common structural motif.
Focusing our attention on the synthesis of anominine (1),4 most
likely the parent structure from which the other metabolites are
biogenetically derived,5 we envisaged a retrosynthetic intermediate
(depicted in Figure 1) embodying the four contiguous stereocenters
of the terpene core and various double bonds that could be used as
flexible handles to introduce further structural complexity. The final
successful route to anominine began with the generation of the two
quaternary stereogenic centers, the one at C20 being set up first by
an asymmetric Robinson annulation of dione 2 (Scheme 1). A
longstanding and unresolved problem in organic synthesis is the
efficient preparation of Wieland-Miescher ketone-type compounds
in high enantioselectivity, thus avoiding multiple purifications and
recrystallizations. In an attempt to address this issue, we carried
out an extensive survey of reaction conditions and organocatalysts.
Starting from 2, we found that 3 could be prepared in highly
enantioenriched form (97% ee) using 2.5% N-Ts-(Sa)-binam-L-Pro
as the catalyst under solvent-free conditions. Furthermore, we found
that this method was general and could be applied to a wide range
of substrates.6 In the most optimized version, in which the catalyst
loading was reduced to just 1%,7 large quantities of the enantioen-
riched building block 3 (96% yield, 94% ee) could be secured. The
high purity of 3 meant that it could be used without purification in
Scheme 2. Synthesis of Key Intermediate 9
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5966 J. AM. CHEM. SOC. 2010, 132, 5966–5967
10.1021/ja101994q  2010 American Chemical Society

C O M M U N I C A T I O N S
only zirconium tetrachloride12 was able to smoothly generate the
coupled product, which after treatment with KF in refluxing EtOH
provided the all-cis diastereomer in which the acetate was simul-
taneously cleaved to give 13 in 84% overall yield. Oxidation with
Ley’s perruthenate followed by Wittig bishomologation of the keto
aldehyde gave 14. Selective olefin cross-metathesis13 upon the
methylene in the side chain and cleavage of the TES group delivered
1, which showed NMR spectroscopic data identical to those reported
for the natural product. The data obtained for 1, [R]D ) -21.0 (c
0.3, MeOH), resulted in the assignment of 1 as ent-anominine and
the absolute configuration depicted in Figure 1 for the natural (+)-
anominine (I) {lit4 [R]D +23.6 (c 0.85, MeOH)}.
Scheme 3. Completion of the Synthesis of (-)-Anominine
In summary, the first synthesis of anominine has been achieved.
Keys to its success were the use of several chemoselective
transformations controlled by the structurally congested nature of
the bicyclic core and the development of a new, highly efficient
method for the synthesis of Wieland-Miescher ketone compounds
that should find wide application in natural product synthesis. This
synthesis opens the way to access other related natural products
from Aspergillus spp. via biomimetic processes, and work in this
direction is now in progress.
Acknowledgment. This work was funded by the MICINN of
Spain-FEDER through Project CTQ-2007-61338/BQU.
Supporting Information Available: Full experimental details and
NMR spectral reproductions for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
ꢀ-aminoketone led to the exocyclic enone, which after chemose-
lective reduction and equilibration yielded stereochemically pure
7. Diastereoselective reduction of ketone 7 under low-temperature
Luche conditions afforded the required alcohol, which under Grieco
conditions gave the allylic selenide 8 set up to undergo a sigmatropic
rearrangement. Once again, the cis-decalin quaternary centers had
a great effect on the outcome of the reaction by not allowing the 8
f 9 rearrangement when the initial oxidation was carried out under
dry conditions. In sharp contrast, the rearrangement in a wet medium
proved to be very effective, giving a stable selenenate that was
readily converted to the key intermediate 9. Presumably, the (S)-
selenoxide depicted in Scheme 2 cannot adopt the required
conformation for the rearrangement process because of steric
hindrance around the C17-Se bond, which is due to the bulkiness
of the o-nitrophenyl group and the methyl group at C15. However,
water-induced epimerization at the Se stereogenic center9 led to
the (R)-selenoxide, which could evolve to 9 through the [2,3]-
sigmatropic rearrangement.
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