A [2 + 2] Photocycloaddition-Fragmentation Approach toward the Carbon Skeleton of cis-Fused Lycorine-type Alkaloids

Article abstract of DOI:10.1021/acs.orglett.8b03402

Starting from isoquinolones, the cis-selective annulation of six-membered rings was possible employing cyclobutenes as olefin components in a [2 + 2] photocycloaddition-fragmentation approach (nine examples, 54-80% yield). The developed sequence enables a

Full text of DOI:10.1021/acs.orglett.8b03402

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A [2 + 2] Photocycloaddition−Fragmentation Approach toward the
Carbon Skeleton of cis-Fused Lycorine-type Alkaloids
Maike H. Wahl, Christian Jandl, and Thorsten Bach*
̈
̈
Department Chemie and Catalysis Research Center (CRC), Technische Universitat Munchen, Lichtenbergstrasse 4, 85747
Garching, Germany
S
* Supporting Information
ABSTRACT: Starting from isoquinolones, the cis-selective
annulation of six-membered rings was possible employing
cyclobutenes as olefin components in a [2 + 2] photo-
cycloaddition−fragmentation approach (nine examples, 54−
80% yield). The developed sequence enables a conceptually
new entry to cis-fused lycorine-type alkaloids of the
Amaryllidaceae family with the complete carbon skeleton
being successfully assembled. A subsequent von Braun-type
reaction emphasized the biological relation between lycorine-
and homolycorine-type alkaloids providing a synthetic tool to
access this class of natural products.
lants from the Amaryllidaceae family belong to the top 20
racemic5 and enantioselective6 fashion. A compound with the
Pmost widely considered medicinal plants, and their putative structure of amarbellisine was synthesized in 2012, but
its analytical data did not match the originally reported data.7
alkaloids have been frequently reported to play important
pharmacological and medicinal roles.1 In the past decades, up
To study the pharmacological and structural features of this
subclass in-depth, we envisioned a conceptually new entry to
members of the Amaryllidaceae family, which gives access to a
variety of cis-fused lycorine-type alkaloids and which is
reported herein. As shown in Scheme 1a, the natural product’s
to 500 highly diversified alkaloids have been isolated that can
be classified into 15 different skeleton types. The most
common among all skeleton types is represented by lycorine-
type alkaloids.2 Usually, the pyrrolo[d,e]phenanthridine
skeleton exhibits a trans-junction between the B and C ring,
but there is a highly interesting subclass showing a unique cis-
configuration (Figure 1). As opposed to the trans-fused natural
products that have been the subject of extensive synthetic
studies,3 there is little known on complete synthetic
approaches to their cis-fused counterparts. Besides γ-lycorane,
which has become a popular target for illustrating the potential
of new synthetic methods,4 fortucine is the only natural
product from that subclass that has been synthesized both in a
Scheme 1. (a) Schematic Retrosynthesis of the Carbon
Skeleton of cis-Fused Lycorine-type Alkaloids; (b)
Envisioned Fragmentation using Appropriate Nucleophiles
either Intra- or Intermolecularly
carbon skeleton can be derived by core modifications and
introduction of the D ring from I. The required cis-fused six-
membered ring can be obtained by fragmentation of tetracycle
II. To allow for a convergent assembly process, we imagined
disconnecting the tetracyclic core II by a [2 + 2] photo-
cycloaddition,8 revealing an isoquinolone and cyclobutene
Figure 1. Representative lycorine-type alkaloids exhibiting a cis-
junction between the B and C ring.
Received: October 24, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03402
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Letter
moiety. In a forward direction, the envisioned approach should
include a photochemically induced [2 + 2] cycloaddition,
followed by a fragmentation.9 Acidic activation of the ester
substituent at the bicyclo[2.2.0]hexane core should allow for
scission of the central σ-bond forming an oxonium ion, which
can be trapped by nucleophiles both intra- and intermolecu-
larly10 allowing access to a wide range of different substitution
patterns (Scheme 1b). To the best of our knowledge, there is
only one example reported using a donor−acceptor substituted
cyclobutene for [2 + 2] photocycloaddition and fragmentation.
In 1992, Smith and co-workers treated a dihydrofuran
derivative with cyclobutene 2a (Scheme 2) in a [2 + 2]
photocycloaddition and induced follow-up fragmentation by
deprotection of the newly formed tertiary alcohol using
tetrabutylammonium fluoride (TBAF).11−13
all isoquinolones) proceeded in an extremely clean reaction
with an excellent yield of 84% (see Supporting Information for
more details). Inducing fragmentation using TBAF, however,
led to oxidation of the product restoring the aromaticity of the
isoquinolone core. Changing to BF3·Et2O in CH2Cl2 (Scheme
2, protocol A, TBS = tert-butyldimethylsilyl, TIPS =
triisopropylsilyl, Piv = pivaloyl) resulted in product 3 and
the cis-selective assembly of the six-membered ring in an
excellent yield of 80%. Similar to the parent isoquinolone 1a,
this sequence worked equally well with isoquinolone 1b,
yielding 4 in 57%. Expanding the scope to the formation of
cyclic acetals upon fragmentation required an intramolecular
nucleophile to trap the intermediate oxonium ion (vide supra).
Cyclobutene 2b was reacted with 1a, 1b, and 1c, and
fragmentation was induced following protocol B to obtain
the cis-assembled products 6, 7, and 5 in 67%, 79%, and 62%
yields, respectively, highlighting its robustness and reliability
across several substrates. Not only was intramolecular trapping
of the oxonium ion feasible, but also the introduction of
external nucleophiles (protocol C) allowed for the formation
of acyclic acetals 9 in 74% yield and 10 in 64%. To achieve
even more versatile building blocks, the ester group was
reduced to the corresponding primary alcohol and mesylated
prior to ring cleavage (protocol D). Thus, a Grob
fragmentation14 became feasible creating an exocyclic double
bond in a 1,4 relation to the acetal. Following this strategy,
methylenecyclohexanes 8 and 11 were obtained in excellent
yields of 54% and 69% over four steps, respectively, accounting
for an average yield per step of 86% and 91%.
Scheme 2. [2 + 2] Photocycloaddition−Fragmentation
a
Sequence To Assemble cis-Fused Six-Membered Rings
In an attempt to apply the five-membered analogue of 2a, we
envisioned extending this transformation to assemble seven-
membered rings cis-selectively. Treatment of 1a with methyl 2-
[(tert-butyldimethylsilyl)oxy]cyclopent-1-ene-1-carboxylate
under photochemical conditions promoted the formation of
the corresponding photoproducts in an excellent yield of 97%.
However, using protocol A to induce the desired fragmentation
was unsuccessful and resulted in the deprotected photo-
products rather than the seven-membered ring. Hence, the
high ring strain energy is crucial for this transformation as its
release is a major driving force.9 Finally, we were also
interested in the significance of substitution patterns on the
cyclobutene moiety. Utilizing a cyclobutene with X = H did
not allow for fragmentation to form a less decorated
cyclohexane unit emphasizing the strict demand for a push−
pull system.
To highlight the utility of the developed procedure, we
aimed to demonstrate its synthetic benefit by a conceptually
new entry to the carbon skeleton of cis-fused lycorine-type
alkaloids.15 We first designed a synthetic route to the A−B−C
tricyclic ring fragment 15 starting from isoquinolone 1c, the [2
+ 2] photocycloaddition−fragmentation sequence precursor
(Scheme 3, Cp* = pentamethylcyclopentadienyl, Ac = acetyl,
Vin = vinyl, Ms = mesyl). The latter was obtained from amide
12 using Raw’s modification16 of Fagnou’s rhodium catalyzed
redox-neutral isoquinolone synthesis.17 Amide 12 itself was
readily prepared starting from commercially available iso-
vanillic acid in two steps and in 60% yield. As described in
Scheme 2, the six-membered ring was established cis-selectively
in 69% yield to give product 11. The dimethoxy acetal was
deprotected using LiBF4 in wet acetonitrile18 and subjected to
a Grignard reaction with the reagent approaching selectively
from the more accessible top face of the molecule, giving rise
to the single diastereoisomer 13 in 82% yield over two steps.
a
(A) BF3·Et2O (CH2Cl2), −40 °C. (B) TMSBr, MeOH (DMF), 0 °C
→ rt. (C) TMSBr or HCl (MeOH), 0 °C → rt. (D). (i) LiBH4
(Et2O), rt, (ii) MsCl, NEt3, (CH2Cl2), 0 °C, (iii) TMSBr, (MeOH), 0
°C.
To evaluate the utility and frontiers of the envisioned [2 +
2] photocycloaddition−fragmentation sequence on isoquino-
lones, we chose a variety of substitution patterns of particular
interest for Amaryllidaceae natural products (Figure 1). All
alkaloids bear either a 9-OH/10-OCH3 (1b or 1c) or a 9,10-
dioxolane (1d) entity on the aromatic core. Interestingly, the
reported fragmentation conditions of Smith and co-workers11
were not suitable for isoquinolones and required modification.
The [2 + 2] photocycloaddition between cyclobutene 2a (as
for all cyclobutenes) and unsubstituted isoquinolone 1a (as for
B
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Letter
The crystal data also showed that the cyclohexane ring adopts
a boat conformation after cyclization, which is stabilized by an
intramolecular hydrogen bond between the secondary and
tertiary alcohol.
Scheme 3. Synthesis of Cyclization Precursor 15 and
Attempted Formation of the Five-Membered Ring
Numerous attempts to directly eliminate the tertiary alcohol
from amide 18 or amine 19 via carbocation formation using
various acids were met with failure. The latter compound was
obtained by LiAlH4 reduction and acetylation in 40% over two
steps (Scheme 5). Attempting a syn elimination to selectively
Scheme 5. (a) Synthesis of Amine 19 and Attempted
Elimination; (b) Proposed Biosynthetic Pathway to
Homolycorine-type Alkaloids with Two Representatives of
this Class
Ozonolysis of both double bonds and reductive quenching
furnished triol 14 in 71% yield. Selective mesylation of the
primary alcohol was achieved in quantitative yield, forming
cyclization precursor 15. During our investigation to form the
missing D ring, we found that oxetane 16 was preferentially
formed under various conditions independent of the basicity of
the applied reagents. With 15 adopting a chair-like
conformation, spatial distance between the amide moiety and
the leaving group would require a conformational flip prior to
substitution. As a consequence, the latter pathway becomes
less likely and oxetane formation prevails (Scheme 3). This
unexpected reactivity stimulated a search for suitable
protecting groups for the secondary and tertiary alcohol
allowing for a single reactivity at the amide unit.
Hence, we were delighted to find that A−B−C−D
tetracyclic product 18 was formed from mesylate 17 by
using trimethylsilyl (TMS) as a protecting group. The
structure of 18 was unambiguously confirmed by single-crystal
X-ray analysis (Scheme 4, Tf = trifluoromethanesulfonyl,
HMDS = hexamethyldisilazide, TFA = trifluoroacetic acid).
enable the double bond in the positions required for the total
syntheses of fortucine and kirkine (see Figure 1), the
established methods remained unsuccessful. Likewise, various
protecting groups on the secondary alcohol at either amide 18
or amine 19 did not allow for the formation of the desired
alkene. After having failed to introduce the double bond by syn
elimination, we turned our attention to procedures for anti
elimination. Triflic anhydride and pyridine in CH2Cl2 at room
temperature yielded a new compound after 1.5 h. Remarkably,
NMR analysis indicated the incorporation of a pyridine unit
into the skeleton. Further structure elucidation by single-crystal
X-ray analysis revealed the formation of product 20 (Scheme
5a, counteranion omitted for clarity). Presumably the tertiary
amine rather than the targeted tertiary alcohol was triflated.
The quaternization allowed for a nucleophilic attack of
pyridine at the benzylic position resembling a von Braun-
type reaction.19 The strained, polycyclic compound 19 is
reminiscent of quinuclidine which displayscompared to
triethylaminea remarkable increase in nucleophilicity at the
amino group.20 Thus, the tertiary amine is more reactive and
Scheme 4. Completion of the Full Carbon Skeleton and Its
Crystal Structure
C
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sterically less hindered than the tertiary alcohol allowing for
this unusual selectivity.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03402.
■
S
In analogy to the observed von Braun-type reaction, there is
a biosynthetic precedent for a C−N cleavage to form III,
which upon rotation and oxidative cyclization generates
lactone IV.2 Along these lines, it is highly intriguing that
lycorine-type alkaloids are intermediates in the biosynthesis of
homolycorines (Scheme 5b). The synthetic importance of this
von Braun-type transformation21 to access the class of
homolycorine-type alkaloids is currently being studied in
more detail and might be applicable to the total synthesis of a
representative member of this natural product class (Scheme
5b, dashed box).
Common to the synthetic strategies to lycorines and
homolycorines is the requirement to obtain the carbon
skeleton of basic structure II in a highly enantioselective
fashion. We have previously shown that [2 + 2] photo-
cycloaddition reactions between isoquinolones and electron
deficient alkenes can be conducted enantioselectively by using
a hydrogen-bonding template (21).22 To our delight, the
coordination of electron-rich isoquinolone 1c and the site-
differentiating attack of a donor−acceptor substituted cyclo-
butene works equally selective with endo-22 being obtained
with 93% ee and exo-22 with 91% ee (Scheme 6, absolute
Experimental procedures, analytical data for all new
compounds, NMR spectra and X-ray data for 18 and 20
(PDF)
Accession Codes
CCDC 1874682−1874683 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: thorsten.bach@ch.tum.de.
ORCID
Thorsten Bach: 0000-0002-1342-0202
Notes
Scheme 6. Enantioselective Version of the [2 + 2]
Photocycloaddition between Isoquinolone 1c and
Cyclobutene 2c Using a Chiral Template
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support by the Fonds der Chemischen Industrie
(Ph.D. fellowship to M.H.W.) is gratefully acknowledged.
■
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