Synthesis of lamellarin alkaloids using orthoester-masked α-keto acids

Article abstract of DOI:10.1039/c8sc05678a

Pyruvic acid and other α-keto acids are frequently encountered as intermediates in metabolic pathways, yet their application in total synthesis has met with limited success. In this work, we present a bioinspired strategy that utilizes highly functionaliz

Full text of DOI:10.1039/c8sc05678a

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Synthesis of lamellarin alkaloids using orthoester-
masked a-keto acids†
Cite this: DOI: 10.1039/c8sc05678a
*
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have been paid for by the Royal Society
of Chemistry
Harry J. Shirley,‡ Maria Koyioni, ‡ Filip Muncan and Timothy J. Donohoe
Pyruvic acid and other a-keto acids are frequently encountered as intermediates in metabolic pathways, yet
their application in total synthesis has met with limited success. In this work, we present a bioinspired
strategy that utilizes highly functionalized OBO (oxabicyclo[2.2.2]octyl) orthoester masked a-ketoacids as
key intermediates for the construction of both type I and II lamellarin alkaloids. Lamellarin D was
synthesized, via a key 1,4-dicarbonyl, in 7 steps and 22% yield from pyruvic acid. Key steps in the
synthesis involve one-pot double enolate functionalisation of 1 followed by double annulation to form
the target pyrrole/N-vinyl pyrrole core and late-stage direct C–H arylation. Lastly, a novel OBO-masked
b-cyano ketone, synthesized from 1, proved to be a valuable intermediate for construction of the type II
lamellarin core via HBr-mediated cyclisation. In this way, lamellarin Q was synthesized in 7 steps and
20% yield from pyruvic acid.
Received 19th December 2018
Accepted 7th March 2019
DOI: 10.1039/c8sc05678a
rsc.li/chemical-science
alkaloids, including work by Jia (2011),4 Chandrasekhar (2017),5
and Yang (2017),6a have been reported.6
Introduction
Pyruvic acid and its a-keto acid derivatives are ubiquitous in
Nature, proven as key intermediates in multiple primary and
secondary metabolic pathways. They are involved in the
formation of amino acids and in the biogenesis of countless
secondary metabolites.7 Indeed, the lamellarins are proposed to
be biogenetically constructed from transamination of 4-
hydroxyphenyl pyruvic acid 3, possibly to the amino acid tyro-
sine, en-route to the type II core, which is itself the biogenetic
precursor to the type I core (Scheme 1).8 Despite the prevalence
of a-keto acids in biogenetic pathways, their use in the total
synthesis of natural products has had limited success, partly
attributed to their instability under basic conditions. This is
The lamellarins are an important family of pyrrole alkaloids
isolated from marine organisms, consisting of around 70
distinct members which are categorised into type I: pentacyclic
skeleton with a fully decorated pyrrole core, or type II: mono-
cyclic skeleton with a 3,4-disubstituted pyrrole core (Scheme 1).1
The biological activities of this family has proven to be nothing
short of remarkable, with lamellarins D, G, H, L and N dis-
playing striking biological assay results.2 Without doubt,
lamellarin D is the lead compound from this catalogue and its
activity has been broadly studied, notably being revealed as
a potent cytotoxin and topoisomerase I inhibitor. Many lamel-
larins have displayed biological effects on both mammalian
cells and viruses, including antiproliferative and multidrug
resistance reversal activity, cytotoxicity, anti-tumour activity and
inhibition of HIV-1 integrase. Given these striking biological
properties coupled with their scarcity in the fragile marine
environment, there has been intense interest in achieving their
total syntheses in order to assist biological assays and SAR
studies.1 In general, routes to the lamellarins have involved
functionalisation of a simple pyrrole core through halogena-
tions and conventional C–C cross couplings or synthesis of
a functionalised pyrrole core from acyclic precursors.3 Recently,
impressive and efficient syntheses of lamellarin D and related
Department of Chemistry, University of Oxford, Chemistry Research Laboratory,
Manseld Road, Oxford, OX1 3TA, UK. E-mail: timothy.donohoe@chem.ox.ac.uk
† Electronic supplementary information (ESI) available: Synthetic procedures,
compounds' characterisation data and NMR spectra. See DOI: 10.1039/c8sc05678a
‡ These authors contributed equally to this work.
Scheme 1 Masked pyruvic acid route to lamellarins D and Q.
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exemplied in early work by Steglich, who described low
yielding routes to lamellarins L9 and G trimethyl ether10 using
pyruvate esters as synthetic starting materials.
Previously, we have demonstrated the synthetic utility of
OBO-ester (oxabicyclo[2.2.2]octyl orthoester) masked a-keto
acid 1 in the construction of 1,4- and 1,5-dicarbonyls, via a Pd-
catalysed enolate arylation/alkylation sequence, and subse-
quent condensation to form aromatic heterocycles, e.g. 2-car-
boxy-pyrroles.11 Inspired by the key role of a-keto acids in
Nature, we envisioned that appropriately substituted OBO-ester
a-keto acids 2 could serve as powerful building blocks with
which to prepare the lamellarin alkaloids. Herein, access to
highly functionalised masked pyruvic acid derivatives via one-
pot enolate arylation and alkylation (e.g. 1 / 2) was achieved.
Subsequent condensation reactions to a pyrrole nucleus under
acidic conditions allowed efficient syntheses of both type I and
II lamellarin cores. This bioinspired strategy allowed short and
high yielding syntheses of lamellarin D (type I) and lamellarin Q
(type II) (Scheme 1). Key advances in the synthesis of the type I
core include double annulation of a 1,4-dicarbonyl with ami-
noacetaldehyde diethyl acetal and late-stage C–H arylation of
the pyrrole core to complete the type I core. Moreover, SNAr
chemistry is used on more than one occasion to allow efficient
syntheses of protected phenols from readily available aryl
uorides.
Scheme 2 Retrosynthetic analysis of lamellarin D.
alkylation of 9 was prepared by O-alkylation of acetovanillone
with 2-bromopropane followed by a-bromination using (Æ)-10-
camphorsulfonic acid/NBS. Treatment of 9 with NaOtBu fol-
lowed by addition of 8 gave the desired 1,4-dicarbonyl 7 in
quantitative yield aer purication. Having established a rst-
generation route to 1,4-dicarbonyl 7, we were keen to explore
a direct one-pot protocol from 1. It was found that 7 could be
prepared in one step from methyl-OBO-ketone 1 by sequential
addition of 10 and 8. Optimal conditions involved initial treat-
ment of methyl-OBO-ketone 1 with NaOtBu in the presence of
Results and discussion
Lamellarin D
Our retrosynthetic analysis of lamellarin D commenced with
a key disconnection of the C-4 aryl group, which would corre-
spond to C–H arylation of pyrrole 5 with aryl bromide 4 using
transition metal catalysis (Scheme 2). We hypothesised that
both the pyrrole and the fused benzenoid ring could be
prepared from a key 1,4-dicarbonyl precursor 7 by reaction with
a suitably substituted amine (e.g. 6) under acidic conditions.
Synthesis of the required 1,4-dicarbonyl 7 would be achieved
using a strategic enolate arylation of OBO-ketone 1, and
subsequent enolate alkylation using a-bromoacetophenone 8.11
A possible one-pot procedure from 1 to 7, by the sequential
addition of 10 and 8 under basic conditions, was envisaged.
Note that 25 g of 1 can be prepared from pyruvic acid in 2 steps
in 44% yield.11a
We set out to synthesise a-aryl OBO-ketone 9 by Pd-catalysed
enolate arylation of methyl-OBO-ketone 1 with aryl bromide 10.
The aryl bromide 10 was itself prepared from commercially
available 4-bromo-5-uoro-2-methoxyphenol (11) by O-
alkylation with 2-bromopropane and subsequent nucleophilic
aromatic substitution (SNAr) at C-5 with sodium benzylate.12
The SNAr route to allow installation of a protected phenol is
much shorter and more efficient than a traditional Baeyer–Vil-
Scheme
3 Synthesis of 1,4-dicarbonyl 7 from 1. Reagents and
conditions: (i) 2-bromopropane (3 eq.), K2CO3 (3 eq.), DMSO, 70 ꢀC,
liger reaction of an aromatic aldehyde (for example, compound 5 h, 97%; (ii) BnOH (4 eq.), NaH (4.6 eq.), NMP, 100 ꢀC, 2 h, 86%; (iii) 2-
bromopropane (1.5 eq.), K2CO3 (2 eq.), DMSO, 55 ꢀC, 3.5 h, 96%; (iv)
10 was synthesized in 5 steps from isovanillin, see ESI Section
(Æ)-10-camphorsulfonic acid (1.9 eq.), NBS (1 eq.), MeCN, 85 ꢀC, 1.5 h,
S1†). Through a short screening process, optimal conditions for
91%; (v) NaOtBu (2.5 eq.), Pd(dtbpf)Cl2 (5 mol%), THF, 50 ꢀC, 24 h, 75%;
the coupling of 1 and 10 were found, using NaOtBu and
(vi) 8 (1.2 eq.), NaOtBu (1.2 eq.), THF, 1.5 h, rt, 100%; (vii) 10 (1 eq.),
NaOtBu (2.5 eq.), Pd(dtbpf)Cl2 (5 mol%), THF, 50 ꢀC, 52 h, then 8 (2 eq.),
Pd(dtbpf)Cl2 (5 mol%) in THF to give 9 in 75% yield
(Scheme 3).11,13 The a-bromoacetophenone 8 required for 30 min, 78%.
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Scheme 4 Synthesis of pyrrole 5. Reagents and conditions: (i) NH4OAc (10 eq.) AcOH, 110 ꢀC, 30 min; (ii) H2, Pd/C, EtOH, rt, 6.5 h; (iii) K2CO3 (2
eq.), EtOH, 90 ꢀC, 2 h, 95% over 3 steps; (iv) BrCH2CH(OEt)2 (6.6 eq.), Cs2CO3 (6.5 eq.), DMF, 110 ꢀC, 24 h, 86%; (v) TfOH (1 M in DCM), DCM, À10
to À5 ꢀC, 24 h, 88%; (vi) 6 (9 eq.), AcOH, H2O (1 mol%), HCO2H (1 mmol%), 100 ꢀC, 16 h, 89%; (vii) 20% Pd(OH)2/C, 1,4-cyclohexadiene (25 eq.),
MeOH/EtOAc, 60 ꢀC, 6 h then K2CO3, 89%.
aryl bromide 10 and Pd(dtbpf)Cl2 (5 mol%) before quenching amine.15 Therefore, treatment of 7 with aminoacetaldehyde
with 8. Protic workup then gave 1,4-dicarbonyl 7 in 78% yield diethyl acetal (6) in glacial acetic acid led to the formation of
aer purication (Scheme 3).
several pyrrole products from which the desired product 14 was
1
Aer establishing a convenient route to 1,4-dicarbonyl 7 in observed by H NMR spectroscopy in small quantities. It was
one step from methyl-OBO-ketone 1, we probed methods for then found that heating 7 at reux in ‘wet’ (1 mol% H2O with 1
condensation to form the pyrrole core. Treatment of 7 with mmol% formic acid) acetic acid delivered 14 in 89% yield. The
NH4OAc in reuxing acetic acid resulted in successful forma- presence of catalytic amounts of water and formic acid likely
tion of the pyrrole core, together with opening of the OBO cage promoted the desired hydrolysis of the OBO-ester and any acetal
to give esters 12 (Scheme 4). Without purication, 12 was intermediate(s). It is noteworthy that this reaction allows
immediately debenzylated using H2 and Pd/C to reveal a phenol construction of both the pyrrole and fused carbocycle ring in
which, upon treatment with K2CO3 in MeOH, underwent lac- a single step.
tonisation to give 13a in 95% yield over three steps. In order to
With successful isolation of 14, the benzyl group was
install the alkene and fused ring motif, N-alkylation of the successfully removed by transfer hydrogenation using Pd(OH)2/
pyrrole using bromoacetaldehyde diethyl acetal was performed, C (Pearlman's catalyst) and 1,4-cyclohexadiene. The phenol
using reported conditions giving 13b as an unstable oil in 86% intermediate was observed by TLC analysis, and quenching of
yield.14 Electrophilic aromatic substitution (SEAr) by treatment the reaction mixture with K2CO3 resulted in rapid lactonisation
of the acetal intermediate 13b with catalytic TfOH,14 and to deliver 5 in 89% yield aer purication.
subsequent in situ elimination then gave N-vinyl pyrrole 5 in
88% yield.
Having devised a route to pyrrole 5 from methyl-OBO-ketone
1 in only three steps, efforts then focused on the envisaged and
Despite this high yielding synthesis of key intermediate 5, key C–H arylation of 5 with aryl halide fragment 4. The synthesis
efforts were also directed towards an alternative and shorter of aryl bromide 4 was accomplished by utilising nucleophilic
retrosynthetic strategy, envisaging installation of two rings aromatic substitution of commercially available 5-bromo-2-
directly from 1,4-dicarbonyl 7 by using an acetal substituted uoroanisole (15) at C-2 with KOiPr (Scheme 5).12b Once more
SNAr chemistry on an unactivated substrate allowed a very short
route to a protected phenol. Initial conditions for C–H arylation
involved treatment of 5 with KOAc, Pd(PPh3) (5 mol%) and aryl
bromide 4 in DMA at 150 C for 16 h.16 Improved yields were
ꢀ
realised by switching the extraction solvent from Et2O to CH2Cl2
and eventually 16 was isolated in 80% yield. It should be noted
that this is the rst late-stage pyrrole C–H arylation in a lamel-
larin alkaloid synthesis; traditional routes to lamellarins have
almost universally used pyrrole halogenation followed by C–C
cross coupling reactions. However, note that impressive early-
stage Rh-catalysed C–H arylation in the synthesis of lamellar-
ins I and C was demonstrated by Yamaguchi and co-workers in
2014.17 Finally, we could then complete the synthesis and access
lamellarin D by using BCl3 to remove all isopropyl ethers.18
Scheme 5 Synthesis of lamellarin D. Reagents and conditions: (i)
iPrOH (4.5 eq.), KOtBu (4.0 eq.), PhMe, DMPU, 80 ꢀC, 30 min, then 15 (1
eq.), 3 h, 82%; (ii) Pd(PPh3)2Cl2 (5 mol%), KOAc (2.0 eq.), 4 (2.5 eq.),
DMA, 150 ꢀC, 22 h, 80%; (iii) BCl3 (1 M in heptane, 9 eq.), DCM, À78 ꢀC
to rt, 3.5 h, 99%.
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This synthesis of lamellarin D over 7 steps and 22% overall
yield from pyruvic acid is short and efficient and compares very
well to others in the literature. Notable steps include di-
functionalisation of methyl-OBO-ketone 1 to the 1,4-dicar-
bonyl 7 in a one-pot procedure, convenient synthesis of
coupling partners 10 and 4 using SNAr reactivity, rapid
construction of the pyrrole and carbocyclic core in a single step
and C–H arylation of late-stage pyrrole intermediate 5. This
synthesis will provide convenient access to lamellarin D and
analogues for biological and pharmaceutical research.
Scheme 7 Synthesis of b-cyano ketone intermediate 18. Reagents
and conditions: (i) 2-bromopropane (1.5 eq.), K2CO3 (2.0 eq.), DMSO,
>99%; (ii) NBS (1.5 eq.), dibenzoyl peroxide (4 mol%), (EtO)2CO, 100 ꢀC,
24 h, 60%; (iii) 19 (1.6 eq.), Pd(dtbpf)Cl2 (5 mol%), NaOtBu (2.5 eq.), THF,
55 ꢀC, 20 h then 20 (1.4 eq.), 3 h, 75%.
Lamellarin Q
Retrosynthetic analysis of lamellarin Q commenced with the
synthesis of C-5 bromopyrrole 17; this could be prepared by an
unusual HBr-assisted cyclisation/aromatisation of b-cyano
ketone 18.19 Debromination could likely be achieved using
standard partial hydrogenolysis conditions (H2, Pd/C), as has
been reported in the literature.20 b-Cyano ketone 18 could be
accessed by employment of the key masked pyruvate function-
alisation strategy (Scheme 6). Treatment of methyl-OBO-ketone
1 with aryl bromide 19 under Pd catalysis and basic conditions
should facilitate enolate arylation and subsequent enolate
quenching with bromo-benzonitrile 20 was envisaged to give 18.
Initial work investigated the desired functionalisation of
methyl-OBO-ketone 1 with aryl bromide 19 and a-bromo benzyl
nitrile 20. Protection of 4-hydroxybenzyl nitrile (21) with 2-bro-
mopropane gave 22 and benzylic bromination using NBS/
dibenzoyl peroxide in diethyl carbonate21 gave 20. Using the
previously developed conditions,11 NaOtBu and Pd(dtpbf)Cl2
(5 mol%) in THF, methyl-OBO-ketone 1 coupled with aryl
bromide 19. Aer 24 h, the enolate was quenched with a-bromo
benzyl nitrile 20 to deliver 18 in 75% yield in one step and as
a single diastereomer (unassigned) aer workup and purica-
tion (Scheme 7).
Scheme 8 Completion of the synthesis of lamellarin Q. Reagents and
conditions: (i) (a) 33% HBr in AcOH, DCM/Et2O (1 : 1), 0 ꢀC to rt, 3.5 h;
(b) K2CO3 (2 eq.), MeOH, 65 ꢀC, 62% over 2 steps; (ii) H2, 10% Pd/C,
NaOAc (2.1 eq.), MeOH, rt, 1 h, >99%; (iii) BBr3 (3 eq.), DCM, À78 ꢀC to
rt, >99%.
With b-cyano ketone intermediate 18 in hand, the key HBr-
assisted pyrrole aromatisation was examined.19 Treatment of
18 with 33% HBr in AcOH in DCM/Et2O as solvent system led to
consumption of starting material (by TLC analysis) in under
20 min, to give a complex mixture of unidentied intermediates
which was simplied aer stirring at rt for 3 h. Aer
neutralisation using K2CO3 and work up, the obtained crude
mixture (which consisted of a mixture of OBO ring-opened
bromo-pyrroles 23) was exposed to MeOH/K2CO3 to give the
methyl bromopyrrole carboxylate 24 in 62% yield, aer puri-
cation. Partial hydrogenolysis with H2 and Pd/C cleanly
removed the bromine atom to give pyrrole 25 and nal removal
of both isopropyl ethers using BBr3 gave lamellarin Q as an
unstable solid (Scheme 8).
Conclusions
To conclude, we have demonstrated the synthetic utility of OBO-
ester masked a-keto acid 1 as a valuable building block for
convenient access to important type I and type II lamellarin
natural products. The bioinspired strategy was accomplished
via the one-pot Pd-mediated arylation and alkylation reaction of
ketone 1 to give either 1,4-dicarbonyl (7) or b-cyano ketone (18)
intermediates. Efficient single step double annulation of 7,
followed by lactone formation and Pd-catalysed direct arylation
Scheme 6 Retrosynthetic analysis of lamellarin Q.
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completed the type I skeleton of lamellarin D, while HBr
promoted aromatisation of 18 provided rapid access to the type
II skeleton of lamellarin Q. These syntheses can be regarded as
short and efficient: lamallarin D and Q were both prepared in
seven steps from pyruvic acid with 22% and 20% yields,
respectively.
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Conflicts of interest
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There are no conicts to declare.
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We thank the EPSRC (EP/P009514/1) for funding this work.
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