A strategic approach to [6,6]-bicyclic lactones: Application towards the CD fragment of DHβE

Article abstract of DOI:10.3762/bjoc.13.98

We report an effective synthetic protocol to access [6,6]-bicyclic lactone moieties through a regio- and stereoselective intramolecular Mizoroki–Heck cross-coupling reaction followed by a 6π-electrocyclization. This method enabled the first synthesis of t

Full text of DOI:10.3762/bjoc.13.98

A strategic approach to [6,6]-bicyclic lactones: application
towards the CD fragment of DHβE
Tue Heesgaard Jepsen‡, Emil Glibstrup‡, François Crestey, Anders A. Jensen
and Jesper Langgaard Kristensen*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 988–994.
Department of Drug Design and Pharmacology, Faculty of Health and
Medical Sciences, University of Copenhagen, Universitetsparken 2,
2100 Copenhagen, Denmark
doi:10.3762/bjoc.13.98
Received: 02 March 2017
Accepted: 11 May 2017
Published: 22 May 2017
Email:
Jesper Langgaard Kristensen* - jesper.kristensen@sund.ku.dk
Associate Editor: D. J. Dixon
* Corresponding author ‡ Equal contributors
© 2017 Jepsen et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
DhβE; Mizoroki–Heck cross-coupling reaction; 6π-electrocyclization;
[6,6]-bicyclic lactone; vinyl halide
Abstract
We report an effective synthetic protocol to access [6,6]-bicyclic lactone moieties through a regio- and stereoselective intramolecu-
lar Mizoroki–Heck cross-coupling reaction followed by a 6π-electrocyclization. This method enabled the first synthesis of the
elusive CD fragment of the Erythrina alkaloid DHβE. Preliminary pharmacological evaluations support the notion that the key
pharmacophores of DHβE are located in the A and B rings.
Introduction
The neuronal nicotinic acetylcholine receptors (nAChRs) have antagonists for the α4β2 nAChR subtype. Although its chemi-
been extensively investigated as potential drug targets for a cal structure has been known for several decades [4,5], no
diverse array of central nervous system (CNS) related medical comprehensive SAR study of DHβE can be found in the litera-
conditions such as Alzheimer’s and Parkinson’s disease, depres- ture, except from our previous deconstruction approach [3] and
sion, ADHD, pain relief, nicotine addiction and drug abuse [1]. a few degradation studies [6,7].
Dihydro-β-erythroidine (DHβE) is a member of the family of
tetracyclic Erythrina alkaloids which were isolated from Balle and co-workers recently published an X-ray structure of
Erythrina species in the end of the 19th century; the majority of the acetylcholine binding protein (AChBP) in complex with
this family possesses neuromuscular blocking effects [2]. DHβE DHβE [8] and based on this structure, two key pharmacophores
is one of the most potent nAChR antagonists of this class and of DHβE were proposed as shown in Figure 1a: the methoxy
displays prominent selectivity for the α4β2 subtype group in the A ring which interacts via hydrogen bonding with a
(Ki = 0.82 µM in a [3H]epibatidine binding assay) [3]. So far, tightly bound water molecule in the protein and the protonated
DHβE represents one of the simplest reference competitive amine which forms hydrogen bonds directly with the backbone
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Figure 1: DHβE and related structures. The Ki values of the compounds at the rat α4β2 nAChR subtype determined in a [3H]cytisine binding assay
are given [3].
of the protein. Thus, this structure indicates that the key phar- wish to provide different strategies used to synthesize the CD
macophores are located in the A ring and the B–C ring, which fragment of DHβE as a general and simple method for the con-
contrasts a mutational-computational study by Bermudez and struction of [6,6]-bicyclic lactones which includes a stereoselec-
co-workers suggesting that the lactone carbonyl is a hydrogen tive synthesis of vinyl halides, a regio- and stereoselective intra-
bond acceptor and hence locating the key pharmacophores in molecular Mizoroki–Heck cross-coupling reaction and a
the C and D rings [9]. In order to weigh these hypotheses 6π-electrocyclization as key steps.
against one another, we have recently published a SAR on the
Results and Discussion
deconstructed AB fragments of DHβE [3]; while reducing the
First strategy with Ts and Cbz protecting
groups
molecular size and complexity considerably, we were able to
retain the affinity, α4β2-subtype selectivity and competitive
antagonist properties in the direct AB-analogue of DHβE (see
Figure 1b). On the other hand, we have previously decon-
structed a selection of aromatic erythrinanes, and interestingly
the SAR showed CD fragments with retained affinity, subtype
specificity, and competitive antagonist property relative to the
parent natural product [10]. Inspired by these results, we
embarked on the synthesis of the CD fragment of DHβE.
As depicted in Scheme 1, our first strategy featured a late stage
installation of the lactonic D ring by a 6π-electrocyclization and
formation of the C ring by an intramolecular Mizoroki–Heck
cross-coupling reaction from a Z-configured olefin which would
be crucial to the stereochemical outcome of the Heck cycliza-
tion event. We envisioned a Z-stereoselective synthesis of a
vinyl halide [17] which should secure the desired E-stereochem-
istry for the Mizoroki–Heck coupling. We were aware that we
would perhaps face a greater challenge in terms of generating
the desired 6-membered exocyclic product rather than the unde-
sired 7-membered endocyclic product [18]. Starting from com-
mercially available propargylamine, tosylated compound 1 was
prepared in 88% yield followed by its alkylation using mesy-
lated homoallylic alcohol to provide 2 in 93% yield. The incor-
poration of the ester functionality proved to be more trouble-
some than anticipated based on literature precedence [19]. After
extensive optimization, it was found that deprotonation of the
terminal alkyne with n-BuLi and subsequent quenching with
Previously, the aromatic CD fragments were straightforwardly
synthesized due to the advantageous reactivity of the aromatic
D ring [10]. However, the syntheses of the lactonic Erythrina
alkaloids are more complex [11,12] as illustrated by more than
150 total syntheses reported for aromatic erythrinanes [2]
whereas only four total syntheses of lactonic erythrinanes have
been published so far [13-16]. Hence, for the DHβE-based CD
fragments, we faced a significantly more challenging synthesis
due to the complex nature of the [6,6]-bicyclic lactone moiety
for which synthetic procedures are extremely scarce. Herein, we
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Beilstein J. Org. Chem. 2017, 13, 988–994.
Scheme 1: First strategy towards the CD fragment (Ts-strategy). i) TsCl, TEA, DCM, 0 °C. ii) NaH, DMF, 0 °C, then 3-buten-1-yl methanesulfonate,
100 °C. iii) n-BuLi, ClCO2Et, THF, −78 °C. iv) LiI, AcOH, 70 °C. v) PdCl2(PPh3)2, Ag2CO3, THF, rt. vi) LiOH, H2O, THF, rt. vii) BHT (cat.), PhMe,
reflux. viii) SmI2. ix) Sodium naphthalenide, DME, −78 °C, then Boc2O, rt. x) TFA, DCM, rt. For more details regarding the failed strategy, see Sup-
porting Information File 1.
ethyl chloroformate provided the desired ester 3 in 43% yield. exo)-5 with LiOH was achieved in 91% yield to furnish
The subsequent stereoselective addition of lithium iodide [17] carboxylic acid 6. The subsequent 6π-electrocyclization per-
provided the Z-vinyl iodide 4 in 76% yield with no trace of the formed in refluxing toluene in the presence of a catalytic
undesired E-isomer.
amount of 2,6-di-tert-butyl-4-methylphenol (BHT) led to
lactone 7 in 83% yield. The removal of the Ts-protecting group
After extensive screening (see Supporting Information File 1 for was initially attempted with SmI2 but unfortunately this reac-
more details), the key Mizoroki–Heck cross-coupling reaction tion proceeded without a trace of the desired lactone 9. Recently
was performed at room temperature providing the desired (E)- Szostak et al. have shown that 6-membered lactones undergo
(6-exo)-5 product in 68% yield using PdCl2(PPh3)2 as catalyst reduction with SmI2 [20] which may explain this result. Howev-
and Ag2CO3 as base in THF. Hydrolysis of the ester (E)-(6- er, upon treatment with sodium napthalenide lactone 7 was fully
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Beilstein J. Org. Chem. 2017, 13, 988–994.
converted but all attempts to isolate and purify the deprotected SAR approach, the route described above was unsatisfactory.
amine 9 were unsuccessful. Therefore, the detosylated amine Therefore we turned our attention to an alternative protecting
was reprotected in situ with Boc2O to provide 8 in 15% yield, group, namely the Cbz group (see Scheme 2). We envisioned
anticipating a clean cleavage of the Boc group to circumvent that the reductive removal of this protective group would allow
subsequent purification of the free amine. Indeed, Boc removal for an easier isolation of the volatile final product. Unfortu-
in the presence of TFA in dichloromethane (DCM) was suc- nately, an alkylation of the Cbz-protected propargylamine 10
cessful and provided, after purification by preparative TLC, the was unsuccessful. To circumvent this issue an initial protection
volatile derivative 9 in 34% (6.5 mg) yield. Although this mate- of the amine 10 using o-NsCl (o-nosyl chloride) led to nosyl de-
rial contained some impurities (see Supporting Information rivative 11 in 98% yield. The subsequent alkylation of 11 with
File 1 for copies of 1H and 13C spectra), it was of sufficient homoallyl bromide provided the o-Ns-protected derivative 12 in
purity for preliminary pharmacological evaluations.
97% yield. A straightforward deprotection–reprotection proce-
dure then furnished the Cbz-protected species 13 in 96% yield.
However, since our aim was to develop a strategy for the late Unfortunately, the attempted functionalization by treatment
stage N-functionalization applicable for a medicinal chemistry with n-BuLi and quenching with ethyl chloroformate led to a
Scheme 2: First strategy towards the CD fragment (Cbz-strategy). i) R-Cl, TEA, CH2Cl2, 0 °C. ii) NaH, DMF, 0 °C, then 3-buten-1-yl methanesul-
fonate, 100 °C. iii) 4-Bromobut-1-ene, K2CO3, DMF, 60 °C. iv) a) p-MePhSH, aq NaOH, CH3CN, 50 °C; b) CbzCl, TEA, DCM, 0 °C to rt. v) LiHMDS,
THF, −78 °C, 1 h, then ClCO2Et, −78 °C to rt. vi) LiHMDS, THF, −78 °C, 2 h, then ClCO2Et, −78 °C, 1 h. vii) LiI, AcOH, 70 °C. viii) PdCl2(PPh3)2,
Ag2CO3, THF, 60 °C. ix) LiOH, H2O, THF, rt. x) BHT (cat.), PhMe, reflux. xi) Pd/C, H2, EtOAc or MeOH or AcOH. xii) Pd(OH)2, H2, EtOAc or MeOH or
AcOH.
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Beilstein J. Org. Chem. 2017, 13, 988–994.
complex mixture of products; the same trend was also observed Second strategy without protecting group
when switching to LDA as the base. When LiHMDS was Since the protective group removal was problematic we decided
applied in this reaction a double addition of ethyl formate took to preinstall the desired N-substituent and thereby avoid any
place giving rise to allenamide 14 as the major product [21]. N-protective group (see Scheme 3). The second strategy started
After extensive optimization, the optimal results were obtained with an N-alkylation of the commercially available N-methyl
by treatment of 13 with 1 equiv of LiHMDS at −78 °C for 2 h propargylamine with homoallyl bromide providing the tertiary
before the addition of 5 equiv of ethyl chloroformate. The re- amine 21 in 69% yield which was used without further purifica-
sulting mixture was then left at –78 °C for 1 h before quenching tion. The subsequent treatment with n-BuLi and trapping with
at low temperature, which proved vital to avoid the allenamide ethyl chloroformate provided alkyne 22 in 72% yield which
formation. The careful control of the reaction conditions in this reacted with LiI in acetic acid furnishing the desired (Z)-vinyl
way provided the desired product 15 in 73% yield and the iodide 23 in 79% isolated yield. A concise screening of the
subsequent Z-stereoselective addition of LiI proceeded without Mizoroki–Heck reaction conditions (which involved Jeffery
problems to give (Z)-16 in 89% yield. Unfortunately, per- conditions [23], Pd2dba3/Xantphos [24] or Fu’s salt [25], and
forming the intramolecular Mizoroki–Heck cyclization at room PdCl2(PPh3)2 in combination with either K2CO3 or Ag2CO3)
temperature using the optimized reaction conditions described revealed that the optimized conditions from the first strategy
above, led to the formation of byproducts. However, carrying still performed quite well for this new approach. Indeed, when
out the cross-coupling reaction at 60 °C afforded the desired using a combination of PdCl2(PPh3)2 as catalyst and Ag2CO3 as
product (E)-17 along with byproduct (Z)-17 (which was base to secure cationic Heck conditions, no trace of the unde-
believed to be the (Z)-6-exo isomer). Hydrolysis of this mixture sired 6-endo product was observed. However, when the reac-
was achieved with LiOH giving carboxylic acids 18 and 19 and tion mixture was heated at 60 °C elimination of HI to form
running the reaction at a 0.01–0.02 molar scale was important alkyne 22 was observed as the major product and at 25 °C and
for it to go to completion overnight. Higher concentrations of 40 °C conversion was very slow. Interestingly, at 50 °C the
the starting material seemed to slow down the reaction, which iodide 23 was selectively converted into the desired (E)-6-exo
also caused hydrolysis of the Cbz group to some extent.
product 24 in 75% isolated yield with only 13% formation of
the elimination product 22, and no trace of the undesired (Z)-6-
The final ring-closure to the CD-ring fragment 20 was success- exo product. The subsequent hydrolysis of the ethyl ester 24 at
fully achieved with 31% yield over 3 steps. Only the desired room temperature smoothly provided carboxylic acid 25 in 81%
(E)-6-exo 18 isomer reacted, leaving the (Z)-exo isomer 19 yield with retention of the E-configuration, whereas isomeriza-
uncyclized, as anticipated. Inspired by the successful Cbz tion of the olefin occurred at higher temperatures.
deprotection of a very similar system [22], the final hydro-
genolysis of the Cbz protecting group with H2 and either Pd/C Subjecting 25 to the standard conditions for the final 6π-electro-
or Pd(OH)2 (up to 50 mol % catalyst loading) in EtOAc, MeOH cyclization (toluene, THF, or DME) at 80–150 °C either led to
or AcOH was attempted, but no trace of the desired lactone 9 no conversion of the starting material or complete decomposi-
was observed. A control experiment with the addition of tosyl tion at elevated temperatures. We speculated that the low solu-
chloride after the hydrogenolysis to form the known tosyl-pro- bility of carboxylic acid 25 in these apolar solvents was the
tected intermediate 7 indicated no signs of product and there- reason. However, addition of small amounts of MeOH in order
fore the CBz strategy was also abandoned.
to increase polarity was detrimental and led to decomposition
Scheme 3: Second strategy towards the CD fragment. i) 4-Bromobut-1-ene, K2CO3, acetone, 70 °C. ii) n-BuLi, THF, −78 °C, 1 h, then ClCO2Et,
−78 °C, 1 h. iii) LiI, AcOH, 50 °C. iv) PdCl2(PPh3)2, Ag2CO3, THF, 50 °C. v) LiOH, H2O, THF, rt. vi) HFIP, 80 °C.
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Beilstein J. Org. Chem. 2017, 13, 988–994.
upon heating. Since the desired cyclization could be also
approached as an intramolecular Michael addition we attempted
to mediate the reaction by applying basic (K2CO3, LiOH) and
acidic (TFA, BF3) conditions but unfortunately this caused
complete decomposition of the starting material upon heating.
However, the cyclization was successful by heating 25 at 80 °C
in the slightly acidic hexafluoro-2-propanol (HFIP). HFIP
seemed exactly acidic enough to mediate the reaction without
causing decomposition. Although 25 was fully converted into a
single product the targeted compound 26 proved to be
extremely difficult to isolate and purify. The compound as the
free amine was very volatile and co-evaporated with different
solvents (HFIP, MeOH, DCM) and was found to be unstable on
silica. Thus, all attempts to purify the material through column
chromatography or preparative TLC led to decomposition of the
material. Also an attempted isolation of the amine as its hydro-
chloride or trifluoroacetate failed. Finally, the [6,6]-bicyclic
Figure 2: The binding affinities of compounds 9 and 26 at the rat α4β2
nAChR. a) The AB fragment was evaluated in a [3H]-epibatidine
binding assay [3]. b) Desmethoxy-βE was evaluated by Wildeboer in a
[3H]-cytisine binding assay [27].
lactone 26 was isolated as a 0.31 mM solution in DMSO after the synthetically challenging [6,6]-bicyclic lactone fragment in
purification by preparative LCMS in a very modest yield of general through an expedient regio- and stereoselective
15% (see Supporting Information File 1 for more details Mizoroki–Heck cyclization approach. This method enabled the
regarding the preparation of the DMSO solution and the calcu- synthesis of the elusive and volatile CD fragments ([6,6]-
lation of its concentration for the pharmacological evaluation). bicyclic lactones 9 and 26) of the Erythrina alkaloid DHβE.
Nonetheless, this route provided us with sufficient material to This allowed the investigation of their pharmacological effects
perform a preliminary pharmacological evaluation. Even though lacking the AB ring substructure present in the parent natural
the purification of our target molecule proved difficult, the product. Even though the CD fragment proved exceedingly
chemistry of the final 6π-electrocyclization was very effective difficult to handle and to purify our results indicate that the
with full conversion of the precursor 25 into the desired [6,6]- absence of the methoxy group on the A ring is detrimental to
bicyclic lactone 26.
the affinity. Further studies concerning the construction of new
designed [6,6]-bicyclic lactones and the deconstruction of the
DHβE scaffold are currently underway in our laboratory.
Pharmacological evaluation
The binding properties of two synthesized CD fragments (com-
pounds 9 and 26) were characterized in a [3H]-epibatidine
binding assay using membranes from HEK293 cells stably
expressing the rat heteromeric nAChR subtypes α4β2, α4β4 and
α3β4 as previously described [10,26]. The pharmacological
evaluation of the CD fragments revealed that the absence of the
methoxy group in the A ring was detrimental to the affinity for
the α4β2 nAChR subtype as depicted in Figure 2 (see Support-
ing Information File 1 for assay details). This contrasts our
recent results obtained for the AB fragments which retained the
affinity comparable to the parent natural product (DHβE), and
indicates that the Balle’s pharmacophore model is the best de-
scription of the key binding interactions of DHβE to α4β2, pro-
vided that the AB and CD fragments bind similar to DHβE in
the active site. This is further supported by Wildeboer’s study
from 2005 who reported a much lower affinity of desmethoxy-
βE compared to the parent DHβE [27].
Supporting Information
Supporting Information File 1
Full experimental details, synthetic procedures,
optimization study, failed strategies and pharmacological
characterization of the compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-98-S1.pdf]
Supporting Information File 2
Copies of NMR spectra.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-98-S2.pdf]
Acknowledgements
The Novo Nordisk Foundation, the Lundbeck Foundation,
Conclusion
Jeppe Juhls Mindelegat and the Danish Council for Indepen-
In summary, we have successfully developed a strategy to dent Research – Medical Sciences are gratefully acknowledged
construct the CD ring system of DHβE and to efficiently access for the financial support.
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Beilstein J. Org. Chem. 2017, 13, 988–994.
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