Angewandte
Chemie
DOI: 10.1002/anie.201200515
Natural Product Synthesis
Total Synthesis of Cyrneine A**
Elangovan Elamparuthi, Cindy Fellay, Markus Neuburger, and Karl Gademann*
The enhancement of cognitive processes and the improve-
ment of memory by drugs or natural products (sometimes
called brain doping) is increasingly performed in our knowl-
edge-based society and is, therefore, a controversial topic.[1]
The identification of such cognitive enhancers is the goal of
many research groups,[2] in particular as such drugs could
open up new therapeutic avenues for the treatment of
neurodegenerative diseases.[3] A hallmark of such diseases is
neuritic atrophy, and compounds inducing or enhancing
neurite outgrowth present interesting lead structures.[3]
During our research efforts on the synthesis and biological
evaluation of such compounds,[4] we became interested in
cyrneine A (1), which enhances neurite outgrowth in pheo-
chromocytoma cells.[5] Detailed investigations on this natural
product suggested a Rac1-dependent mechanism.[6] Herein,
we report the first total synthesis of cyrneine A (1).
Cyrneine A (1) features a tricyclic 5-
The total synthesis of cyrneine A (1) started with the
preparation of the five-membered fragment 5, which already
included the correct functionalization both with regard to the
stereocenters as well as for the subsequent Knoevenagel and
Heck reactions (Scheme 1). (ꢀ)-Carvone was reduced
according to a literature procedure,[8] and the resulting OH
function was protected with a TBS group. The exocyclic
double bond was easily reduced by H2 and PtO2, and the
protected alcohol 2 was obtained in 96% yield over three
steps. The ring contraction to the five-membered substrate
was achieved by ozonolysis[9] and reductive work-up (Zn in
acetic acid) via 3, and a subsequent cyclization mediated by
piperidinium acetate. Reduction of the resulting cyclopentene
carboxyaldehyde to the alcohol followed by transetherifica-
tion[10] gave vinyl ether 4. The quaternary stereogenic center
was established by a Claisen rearrangement[10] in a sealed tube
(toluene, 1758C), and the resulting aldehyde 5 was obtained
in 81% yield. Thus, access to this building block was secured
in 8 steps and 55% calculated overall yield.
6-7 ring system containing a hexatrienal
unit. In addition, the quaternary stereo-
genic centers at C6 and C9 with the
angular methyl groups pose a synthetic
challenge, which is complemented by
the two neighboring stereogenic centers.
The Knoevenagel condensation of the aldehyde 5 with
cyclohexa-1,3-dione was readily carried out in the presence of
l-proline as the catalyst. The unsaturated intermediate was
reduced in situ by the Hantzsch ester to prevent multiple
additions of the nucleophile.[11] Interestingly, the stability of
the product from this sequence is limited and, therefore, the
intermediate was alkylated immediately with methyl iodide
and DBU. The resulting diketone 6 was characterized by X-
ray crystal-structure analysis.[12] It was found after tedious
experimentation that the introduction of the oxygen func-
tionality for the Heck reaction was best carried out at this
stage: Ozonolysis gave the triketone 7 (X-ray crystal struc-
ture).[12] After scouting multiple routes, we realized that the
stereoselective installment of the quaternary center at C6 was
only feasible at this stage. The diastereoselective reduction of
the triketone 7 under Luche conditions[13] resulted in high
Cyrneine A (1) is a member of the
cyathane diterpenes, of which several successful synthetic
strategies have been published.[7] We opted for a convergent
synthetic strategy, which would join the five- and seven-
membered rings through a reductive Knoevenagel condensa-
tion and a Heck cylization. Additional interesting steps would
include a Yamamoto ring expansion reaction and a palla-
dium-mediated reductive carbonylation.
[*] Dr. E. Elamparuthi, Prof. Dr. K. Gademann
Department of Chemistry, University of Basel
National Centre of Competence in Research “Chemical Biology”
St. Johanns-Ring 19, 4056 Basel (Switzerland)
E-mail: karl.gademann@unibas.ch
regioselectivity, and the 5R,6R diastereoisomer
8 was
obtained as the major product in a ratio of 4.25:1, with none
of the unlike diastereoisomers observed (for details, see the
Supporting Information).
The selectivity of this transformation is very remarkable,
as only one carbonyl group of the triketone is selectively
C. Fellay
Swiss Federal Institute of Technology (EPFL)
1015 Lausanne (Switzerland)
=
attacked from one face. The cyclopentanone C O group
Dr. M. Neuburger
Laboratory for chemical crystallography, University of Basel
Spitalstrasse 51, 4056 Basel (Switzerland)
appears to be sterically too hindered for a successful attack.
The relative facial selectivity resulting in the like configu-
ration can be explained by the use of Luche reagents.[14] The
preference for one carbonyl group of the cyclohexadione
(regioselectivity) must reside in the presence of the stereo-
genic centers of the cyclopentane ring, and the transfer of
stereochemical information over at least four bonds could, for
[**] K.G. is a European Young Investigator (EURYI). We thank the SNF
for financial support (PE002-117136/1), and C. Daeppen and C.
Hugelshofer for excellent technical support. A part of this work was
supported by a Novartis Early Career Award (to K.G.). We thank
Prof. Dr. Maria Carla Marcotullio for a copy of the NMR spectrum of
1.
example, be explained by transient complexation/cyclization
[15]
=
via the C4 O group during the course of the reaction.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2012, 51, 4071 –4073
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4071