A Conia-Ene-Type Cyclization under Basic Conditions Enables an Efficient Synthesis of (?)-Lycoposerramine R

Article abstract of DOI:10.1002/anie.201610021

An enantioselective total synthesis of the Lycopodium alkaloid lycoposerramine R is presented. It relies on a base-mediated cyclization that resembles the Conia-ene reaction of ynones and gold-catalyzed variants thereof. Thus, hydrindanones and other functionalized ring systems bearing an exocyclic alkene can be rapidly accessed at room temperature without noble metal catalysis or substrate preactivation.

Full text of DOI:10.1002/anie.201610021

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Communications
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International Edition: DOI: 10.1002/anie.201610021
German Edition: DOI: 10.1002/ange.201610021
Total Synthesis
A Conia-Ene-Type Cyclization under Basic Conditions Enables an
Efficient Synthesis of (ꢀ)-Lycoposerramine R
Felix W. W. Hartrampf, Takayuki Furukawa, and Dirk Trauner*
Abstract: An enantioselective total synthesis of the Lycopo-
dium alkaloid lycoposerramine R is presented. It relies on
a base-mediated cyclization that resembles the Conia-ene
reaction of ynones and gold-catalyzed variants thereof. Thus,
hydrindanones and other functionalized ring systems bearing
an exocyclic alkene can be rapidly accessed at room temper-
ature without noble metal catalysis or substrate preactivation.
C
arbon–carbon triple bonds combine high enthalpies of
formation and low steric hindrance with remarkable kinetic
inertness, which can be overcome, however, though appro-
priate activation. As such, they are very useful functional
groups for the construction of complex molecular frameworks
in multistep syntheses.[1] Indeed, alkynes have seen increasing
use in synthesis, fueled by the development of transition-
metal-catalyzed reactions that rely on the p-acidity of metals
such as gold and platinum.[2] Recently, alkyne metathesis
reactions and stereoselective trans-additions to alkynes have
further increased the synthetic value of these venerable
functional groups.[3]
Although their chemistry is now well developed, alkynes
are occasionally found to react in unintended ways. During
our studies towards the synthesis of lycopodine-type Lycopo-
dium alkaloids, we sought to transform a terminal alkyne into
an internal one under basic conditions.[4] To this end, we
treated compound 1 with three equivalents of potassium tert-
butoxide in dimethyl sulfoxide and observed a clean reaction
that went to completion within 30 minutes. The product,
however, turned out to be cis-hydrindane 3 bearing an exo-
methylene group instead of the intended internal alkyne 2
(Scheme 1A). In essence, this cyclization represents a variant
of the classic thermal Conia-ene reaction discovered in the
1970s (Scheme 1B).[5] This reaction occurs only under harsh
thermal conditions (250–4008C) due to the unfavorable
equilibrium between the keto and enol tautomers. More
recently, gold-catalyzed versions have emerged that require
additional activation as a b-keto ester (6!7) or a silyl enol
ether (8!9).[6] Reports on transition metal free, base-
Scheme 1. Reaction discovery and previous related examples.
mediated carbocyclizations using unactivated alkynes are
rare, with the notable exception of Dixonꢀs study on
Daphniphyllum alkaloids (10!11) and earlier work by
Taguchi involving malonates.[7] This prompted us to inves-
tigate our cyclization more systematically. We were also well
aware that hydrindanes such as 3 would be of great interest
for the synthesis of Lycopodium alkaloids, especially of the
fawcettimine subclass.[8]
To identify the best conditions for the cyclization we chose
ynone 12 as a model substrate. A screen of different bases in
DMSO showed that potassium tert-butoxide was indeed the
most efficient promoter of the reaction. Other bases such as
potassium hydroxide, ethoxide, and hexamethyldisilazide
provided the product in significantly lower yield (Table 1,
entries 2–4) or gave rise to product mixtures. Other counter-
ions proved inferior with respect to reaction times and yields
[*] F. W. W. Hartrampf, T. Furukawa, Prof. Dr. D. Trauner
Department of Chemistry
Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5–13, 81377 Mꢁnchen (Germany)
E-mail: dirk.trauner@lmu.de
T. Furukawa
Department of Applied Chemistry, Faculty of Engineering
Osaka University
Suita, Osaka 565-0871 (Japan)
Supporting information and the ORCID identification number for
one of the authors of this article can be found under http://dx.doi.
org/10.1002/anie.201610021.
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Table 1: Reaction development.
Table 2: Substrate scope.
Entry Base
Equiv. Solvent
Reaction NMR yield
time [h]
[%][a]
1
2
3
4
5
6
7
8
KOt-Bu
KOEt
KOH
KHMDS 1.0
NaOt-Bu 1.0
1.0
1.0
1.0
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
0.5
0.5
24
5
71 (65)
65
3
57
47
0
69
66
56
18
4
2
LiOt-Bu
KOt-Bu
1.0
0.2
16
16
3
0.5
16
24
1
KOt-Bu[b] 0.2
9
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
3.0
1.0
3.0
1.0
10
11
12
13
THF
THF/DMSO (1:1)
THF
70
6
KOt-Bu[c] 1.0
16
[a] Yield of isolated product in brackets. [b] 0.2 equiv. 18-crown-6 was
added. [c] 3.0 equiv. DMSO was added.
(entries 5 and 6), as did other solvents or solvent mixtures
(entries 10–13). Substoichiometric amounts of base also led to
clean product formation but did not improve the yields. The
addition of 18-crown-6 improved the rate, but had little if any
effect on the yield. Under all conditions surveyed, the cis-
hydrindane 13 was the only diastereomer observable by
1H NMR spectroscopy. To exclude possible catalysis from
trace metals contained in the reagent or the substrate
prepared via cuprate addition, we confirmed the absence of
all metals commonly used in alkyne activation by ICP-AES.
With optimal conditions identified, we set out to inves-
tigate the scope and limitations of our method with a variety
of substrates (Table 2). We typically used one equivalent of
KOt-Bu in each case since it provided the cleanest reaction
profile, unless stated otherwise. Cyclic ketones bearing
various a-alkyl groups could be cyclized to afford compounds
bearing a quaternary stereocenter (entries 1–5). As demon-
strated in entries 4 and 5, both tertiary and secondary
carbamates are tolerated. As an example of a nonterminal
alkyne, alkynyl chloride 24 could be converted to the
synthetically useful vinyl chloride 25, which was obtained
exclusively as the cis isomer. This matches Taguchiꢀs analo-
gous cyclization involving malonates.[7b]
By substituting a-alkyl for a-aryl groups, benzylic quater-
nary stereocenters could be furnished as well (entries 8 and
9). Frameworks other than hydrindanes could also be
accessed, such as the spiro compounds 23 and 31. Notably,
the pulegone-derived alkyne 22 cyclized smoothly to establish
two adjacent quaternary carbons (entry 6) in good yield. We
were also able to expand our method to heterocyclic systems.
Oxindole 30 cleanly underwent the cyclization to give spiro
compound 31, whose single-crystal X-ray structure is shown in
the Supporting Information. Tetrahydroquinolinone 32 was
also a viable substrate, affording the functionalized tricycle
33, albeit in moderate yield.
[a] 2.0 equiv. KOt-Bu was used. [b] NMR yield, preferably isolated as the
Boc-protected oxindole. See the Supporting Information for details.
The reaction also worked well when cyclic ketones
without a-substituents were used. In this case, the exocyclic
double bonds isomerized under the basic conditions to yield
conjugated enones, as had been observed previously by Dixon
(Table 3).[7a] Overall, this transformation is reminiscent of an
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Table 3: Cyclization with concomitant double bond isomerization.
[a] 4:1 mixture of exo/endo isomers favoring the enone.
intramolecular aldol condensation, but it can be carried out
with acid-sensitive substrates such as 34.
With the insight gained from these substrates, we returned
to our initial goal of developing a short synthesis of
Lycopodium alkaloids. We deemed our hydrindanone syn-
thesis well suited to access the fawcettimine family, in
particular lycoposerramine R. This tetracyclic alkaloid,
which bears four stereocenters including a quaternary one,
was isolated by Takayama and co-workers from Lycopodium
serratum in 2009.[9] Due to its rather unusual structure, which
also features an a-pyridone, it has attracted significant
synthetic interest.[10] This has so far resulted in racemic
syntheses by the Sarpong[10a] and Takayama[10b] groups as well
as an enantioselective synthesis by the latter.[10c] The key
quaternary stereocenter was set by Eschenmoser–Claisen,
Diels–Alder, and alkylation reactions, respectively, in these
studies. The total number of steps ranged from 13 for the
shortest racemic synthesis to 17 for the enantioselective
synthesis. We reasoned that our method would allow for
a more rapid enantioselective synthesis starting from a-iodo
ketone 40, a popular building block in the synthesis of
Lycopodium alkaloids.[11] Our synthesis began with a B-alkyl
Suzuki reaction of N-Boc-allylamine (41) and iodoenone 40,
delivering enone 42 in high yield.[12] Cuprate addition of the
known Grignard reagent 43 proceeded as planned, yielding
the cyclization precursor 20 in very high overall yield after
double desilylation (Scheme 2).
The ensuing cyclization furnished the desired hydrinda-
none 21 in 62% yield. Allylic oxidation of 21 to enone 44
could be carried out in a one-pot procedure using SeO2/
TBHP, followed by Dess–Martin oxidation. The transforma-
tion of the enone into an a-pyridone proved to be quite
challenging due to competing decomposition under a variety
of conditions.[13] Eventually, a modification of the classic
Krçhnke reaction gave the desired pyridone: heating enone
44 with acetamide derivative 45 for an extended time and at
elevated temperature provided 46, which was used directly in
the ensuing steps.[14] A Boc carbamate deprotection followed
Scheme 2. A) Total synthesis of lycoposerramine R; B) Synthesis of
Overman’s sieboldine A intermediate. See the Supporting Information
for detailed procedures.
by reductive amination could be carried out as a one-pot
procedure to give lycoposerramine R as a single diastereomer
in 35% overall yield from enone 44. Our synthetic compound
was identical in all respects with the natural material isolated
by Takayama.[9] The key disconnection also proved useful in
the synthesis of hydrindanone 17, obtained with a route
similar to 21. Compound 17 was readily converted into enone
48 in three steps via hydrindanone 47. This allowed us to
intercept Overmanꢀs elegant route to sieboldine A,[15] which
hinges on Prins pinacol chemistry to furnish the hydrin-
dane.[16] With our route, intermediate 48 can be accessed in 8
steps from commercial starting materials, which compares
favorably with the 16 steps of the original route.
In summary, a convenient base-mediated cyclization has
been developed that gives access to useful polycyclic building
blocks. The reaction is particularity well-suited for the
construction of quaternary stereocenters next to carbonyl
groups in a variety of ring systems. Notably, it occurs at room
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temperature without the need for preactivation of the
substrate or transition metal catalysis. The exact mechanism
of this reaction remains to be determined and will be the
subject of detailed analysis, both on the theoretical and the
experimental level. We have successfully applied our method-
ology to the synthesis of lycoposerramine R, resulting in the
most concise asymmetric synthesis to date (7 steps from
a known iodoenone). In addition, an intermediate of Over-
manꢀs sieboldine A synthesis was obtained, shortening the
sequence significantly. Applications of this chemistry to the
synthesis of other alkaloids are under investigation and will be
reported in due course.
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Acknowledgements
We thank Giulio Volpin, Nina Vrielink, Benjamin Williams,
Dr. Bryan Matsuura and Dr. Hong-Dong Hao for helpful
discussions during the preparation of this manuscript. We
acknowledge Stephan Heß and Christian Steinborn for
experimental assistance and JSPS for a JSPS Research
Fellowship for Young Scientists for T. Furukawa.
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The authors declare no conflict of interest.
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Keywords: alkynes · Conia-ene reaction · hydrindanes ·
lycopodium alkaloids · total synthesis
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Manuscript received: October 13, 2016
Final Article published: && &&, &&&&
4
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Communications
Total Synthesis
An enantioselective total synthesis of the
Lycopodium alkaloid lycoposerramine R
relies on a base-mediated cyclization that
resembles the Conia-ene reaction of
ynones and gold-catalyzed variants
thereof. Thus, hydrindanones and other
functionalized ring systems bearing an
exo-methylene group can be rapidly
accessed at room temperature without
noble metal catalysis or substrate preac-
tivation.
F. W. W. Hartrampf, T. Furukawa,
D. Trauner*
&&&& — &&&&
A Conia-Ene-Type Cyclization under Basic
Conditions Enables an Efficient Synthesis
of (ꢀ)-Lycoposerramine R
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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