A photoinduced cyclization cascade - Total synthesis of (-)-leuconoxine

Article abstract of DOI:10.1002/chem.201500656

A protecting-group-free and enantioselective total synthesis of the monoterpenoid indole alkaloid (-)-leuconoxine was accomplished. The key step comprises a novel photoinduced domino macrocyclization/transannular cyclization involving the Witkop cyclization, for which additional mechanistic evidence is provided. This process furnishes a diaza[5.5.6.6]fenestrane skeleton, which is a hitherto unprecedented structure element.

Full text of DOI:10.1002/chem.201500656

DOI: 10.1002/chem.201500656
Communication
&
Natural Products
A Photoinduced Cyclization Cascade—Total Synthesis of
(À)-Leuconoxine
Magnus Pfaffenbach and Tanja Gaich*[a]
In memory of Prof. Dr. rer. nat. Dr. h. c. Ekkehard Winterfeldt
cascade of linear precursor 4, which forms three of the four
rings of the fenestrane in a single chemical transformation to
give compound 3.
Abstract: A protecting-group-free and enantioselective
total synthesis of the monoterpenoid indole alkaloid (À)-
leuconoxine was accomplished. The key step comprises
a novel photoinduced domino macrocyclization/transan-
nular cyclization involving the Witkop cyclization, for
which additional mechanistic evidence is provided. This
Besides leuconoxine and its structural siblings leuconodines
A–F[7] and melodinine E,[8] the fenestrane structure motif is
only reported in three other natural products: laurenene,[9] the
penifulvins such as penifulvin A,[10] and asperaculin A[11]—all of
them are terpenes. To the best of our knowledge, the leuco-
noxine subgroup represent the first alkaloids containing a fen-
estrane structure motif. This exceptional feature prompted us
to engage in their total synthesis to develop an elegant and
concise access to this intriguing diazafenestrane system 2.
Structure analysis of leuconoxine (1) revealed two major syn-
thetic challenges: 1) A stereogenic quaternary carbon center;
and 2) the central diazaspiro aminal center C-21 (Figure 1).
With these constraints, we turned our attention to a photo-
chemical reaction for the formation of the ABC-ring system—
the Witkop cyclization.[12] This reaction constitutes a photo-
chemical CÀH activation avoiding prefunctionalization of the
molecule and facilitating a protecting-group-free synthesis.[13]
As shown in Figure 1, we started our retrosynthetic analysis by
disconnection of ring D. This leads to compound 3, which har-
bors the ABC ring system of the natural product. A photo-
chemical induced Witkop-/transannular cyclization cascade of
amide 4 in a single step then affords the tricyclic ABC ring
system of 3. The Gassman protocol[14] was chosen for the syn-
thesis of 2-substituted indole 5. The chiral quaternary carbon
center is obtained from known b-ketoester 6, which can be
prepared in three steps from commercially available ethyl 2-
ethylacetoacetate following Suemune’s protocol.[15]
process furnishes
a diaza[5.5.6.6]fenestrane skeleton,
which is a hitherto unprecedented structure element.
The plant family Apocynaceae produces a broad spectrum of
biologically active monoterpenoid indole alkaloids.[1] Among
them, the leuconolam–leuconoxine–mersicarpine alkaloid
family has been isolated from several Apocynaceae species.[2–4]
It has immediately drawn significant attention from the syn-
thetic community, which is reflected by four completed total
syntheses in the last two years.[5] Leuconoxine (1) is character-
ized by its signature structure element, a hitherto completely
unprecedented diaza[5.5.6.6]fenestrane system 2,[6] consisting
of the ABCD rings (Figure 1). In comparison with the complet-
ed syntheses, our retrosynthetic planning involves a cyclization
Our total synthesis commenced with the preparation of b-
ketosulfide 7, which is required for Gassman indole synthesis.
For this purpose, methyl ketone 6 was first converted to the
corresponding bromoketone, which was then refluxed in SMe2
to provide 7 in 90% yield. Gratifyingly, exposure of sulfide 7 to
N-chloroaniline at À458C, followed by NEt3 treatment and
acidic work-up, afforded the 3-(methylthio)indole 8 in 77%
yield (Scheme 1). With indole 8 in hand, preparation of the
requisite a-chloroacetamide moiety for Witkop cyclization was
now envisioned. Since standard desulfurization with Ra-Ni led
to complex product mixtures, selective removal of the sulfide
group in the presence of the allyl double bond was accom-
plished in 88% yield using thiosalicylic acid in TFA.[16] Elonga-
tion of the tether-chain was accomplished through a three-
step sequence involving DIBAL-H reduction, Parikh-Doering ox-
idation, and Wittig olefination to generate a,b-unsaturated ni-
Figure 1. Retrosynthetic analysis for leuconoxine (1).
[a] M. Pfaffenbach, Dr. T. Gaich
Institute of Organic Chemistry, Leibniz University of Hannover
Schneiderberg 1b, 30167 Hannover (Germany)
E-mail: tanja.gaich@oci.uni-hannover.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500656.
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ratio. In accordance with the accepted mechanism of the
Witkop reaction, the domino sequence is initiated by a photoin-
duced electron transfer (PET) from the excited state of the
indole chromophore to the chlorocarbonyl moiety generating
intermediate 15 (Scheme 3). Loss of a chloride anion leads to
diradical cation 16, which undergoes cyclization with the aro-
matic ring to yield cation 17. Instead of rearomatization of 17,
transannular iminium ion trapping occurs, affording advanced
intermediate 3. In this way, for the first time we are able to
provide experimental evidence for the proposed iminium ion
17 as an intermediate in the Witkop cyclization. The develop-
ment of this domino macrocyclization/transannular cyclization
yields three of the four rings of the diaza[5.5.6.6]fenestrane
system along with the sensitive aminal functionality.
Scheme 1. Preparation of the Witkop cyclization precursor. Reagents and
conditions: a) NEt3, TMSOTf, CH2Cl2; NBS, THF; SMe2, toluene, 808C, 90%;
b) aniline, À458C, CH2Cl2, MeCN, tBuOCl, then NEt3, then H3PO4, 77%; c) TFA,
thiosalicylic acid, 88%; d) DIBAL-H; DMSO, SO3·pyr; Ph3P=CHCN, toluene,
808C, 73% (3 steps); e) Mg, MeOH, 85%; f) LiAlH4, Et2O; g) 10, DIC, DMAP,
73% (2 steps); h) BH3·SMe2, THF, then NaBO3, 51%. NBS=N-bromosuccini-
mide, TFA=trifluoroacetic acid, DIBAL-H=diisobutylaluminium hydride,
DIC=N,N’-diisopropylcarbodiimide, DMAP=4-dimethylaminopyridine.
To improve the diastereoselectivity in favor of 3, we protect-
ed the hydroxyl group of 4 with bulky silyl groups such as
TBDPS or TIPS. Interestingly, this changed the ratio of 14 and 3
in favor of the undesired isomer (14:3=1.4–1.5:1). Assuming
that solvents with high dielectric constant might beneficially
trile 9 in 73% yield. Reduction of 9 using Mg/MeOH
(85% yield), followed by LAH yielded the correspond-
ing amine, which was trapped in situ with 2-chloro-
acetic acid (10) to give a-chloroacetamide 11 in 73%
yield over two steps. Finally, a sequence of hydrobo-
ration–oxidation afforded linear Witkop precursor 4
in 17% overall yield starting from known 6. This syn-
thetic route was routinely carried out on multigram
Scheme 3. Proposed mechanism of the domino cyclization sequence.
scale and requires only six chromatographic purifica-
tions.
Having established an efficient route to precursor
4, we started to explore the proposed Witkop photocyclization.
Since 2-substituted indoles preferentially cyclize to the 3-posi-
tion yielding 2,3-annulated products, we expected that irradia-
tion of 4 at 254 nm would generate this CÀC-bond. To our sur-
prise, we obtained (2,4)indolophane 12 and (2,7)indolophane
13 as the major products instead, resulting from cyclization to
the C4- and C7-indole positions (Scheme 2). Additionally, two
minor products were formed in 10% combined yield. Careful
structure elucidation of these two products revealed structures
14 and 3, which are diastereomers and were obtained in a 1:1
stabilize the charged intermediates involved in the reaction,
we also examined aqueous methanol and acetonitrile based
solvent systems. These conditions gave comparable ratios of
the domino reaction products 14 and 3, yet with decreased
overall yield. Furthermore, the use of sodium carbonate as
base proved to be crucial, since the reaction in the presence of
lithium carbonate exclusively afforded the two eleven-mem-
bered ring indolophanes 12 and 13. Of the two diastereomers
formed in this process, only 3 can undergo final d-lactam for-
mation. With reasonable amounts of 3 in hand, we thus oxi-
dized the hydroxyl group with TPAP/NMO to give aminal 18,
thereby closing ring D and establishing the fenestrane system,
which upon second oxidation in situ furnished (À)-leuconoxine
(1) in 50% yield (Scheme 4). The spectroscopic data were iden-
tical to those reported in the literature [3,5].
Scheme 4. Total synthesis of (À)-leuconoxine (1). Reagents and conditions:
j) TPAP, NMO, MeCN, 50%. TPAP=tetrapropylammonium perruthenate,
NMO=N-methylmorpholine N-oxide.
Scheme 2. Products of the Witkop cyclization of 4. Reagents and conditions:
i) hn (254 nm), Na2CO3, MeOH, rt, 49%.
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In conclusion, we have accomplished a concise, enantiose-
lective total synthesis of (À)-leuconoxine in only eight isolated
steps from known b-ketoester 6 without the requirement of
protecting groups, albeit in low yields for the photo-reaction,
and an overall yield of 0.5%. Our synthesis features a photoin-
duced domino macrocyclization/transannular cyclization pro-
cess, which constructs three of the four rings of the dia-
za[5.5.6.6]fenestrane skeleton in one single operation. The fen-
estrane scaffold is unprecedented, and therefore our method
provides a direct and mild access to this signature structure el-
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Keywords: fenestrane · indole alkaloid · total synthesis ·
transannular cylization · witkop photocyclization
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Received: February 16, 2015
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COMMUNICATION
&
Natural Products
M. Pfaffenbach, T. Gaich*
&& – &&
A Photoinduced Cyclization Cascade—
Total Synthesis of
(À)-Leuconoxine
A signature structure element: A pho-
toinduced domino macrocyclization/
transannular cyclization was developed
for the enantioselective and protecting-
group-free total synthesis of the mono-
terpenoid indole alkaloid (À)-leuconox-
ine. This process furnishes the unprece-
dented diaza[5.5.6.6]fenestrane structure
element from a simple, linear precursor
in two chemical transformations, also
providing additional evidence for the
proposed mechanism of the Witkop
cyclization.
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4
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!