Asymmetric Construction of Alkaloids by Employing a Key ω-Transaminase Cascade

Article abstract of DOI:10.1002/chem.202000067

An ω-transaminase-triggered intramolecular aza-Michael reaction has been employed for the preparation of cyclic β-enaminones in good yield and excellent enantio- and diastereoselectivity, starting from easily accessible prochiral ketoynones and commercially available enzymes. The powerful thermodynamic driving force associated with the spontaneous aza-Michael reaction effectively displaces the transaminase reaction equilibrium towards product formation, using only two equivalents of isopropylamine. To demonstrate the potential of this methodology, this biocatalytic aza-Michael step was combined with annulation chemistry, affording unique stereo-defined fused alkaloid architectures.

Full text of DOI:10.1002/chem.202000067

A Journal of
Accepted Article
Title: Asymmetric Construction of Alkaloids Employing a Key ω-
Transaminase Cascade
Authors: Freya Taday, James Ryan, Stephen P. Argent, Vittorio
Caprio, Beatriz Maciá, and Elaine O'Reilly
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.202000067
Link to VoR: http://dx.doi.org/10.1002/chem.202000067
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10.1002/chem.202000067
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COMMUNICATION
Asymmetric Construction of Alkaloids Employing a Key ω-
Transaminase Cascade
Freya Taday,[a] James Ryan,*[a,c] Stephen P. Argent,[a] Vittorio Caprio,[b] Beatriz Maciá,[b] Elaine
O’Reilly*[a,c]
Abstract: An ω-transaminase triggered intramolecular aza-Michael
reaction has been employed for the preparation of cyclic β-
enaminones in good yield and excellent enantio- and
diastereoselectivity, starting from easily accessible prochiral
ketoynones and commercially available enzymes. The powerful
thermodynamic driving force associated with the spontaneous aza-
Michael reaction effectively displaces the transaminase reaction
equilibrium towards product formation, using only two equivalents of
isopropylamine. To demonstrate the potential of this methodology, we
have combined this biocatalytic aza-Michael step with annulation
chemistry, affording unique stereo-defined fused alkaloid
architectures.
traditional synthetic chemistry. The growing biocatalyst toolbox
means that enzymes can now be considered alongside other
homogeneous catalysts, and this has facilitated the concept of
biocatalytic retrosynthesis.[17] The prevalence of chiral amines in
bioactive natural products and pharmaceutical drugs has led to
considerable interest in the development and application of
transaminase (TA) enzymes for their synthesis.[18] TAs belong to
fold types I and IV of pyridoxal 5-phosphate (PLP)-dependent
enzymes and catalyse the reversible transfer of an amino group
from a suitable donor to a carbonyl acceptor. While α-TAs
exclusively convert α-amino and α-keto acids, ω-TAs can
accommodate substrates with
a distal carboxylate group.
Perhaps the most synthetically interesting subgroup of ω-TAs are
the amine TAs (ATAs), which are capable of accepting substrates
lacking a carboxylate group. These enzymes are of considerable
interest due to their potential for the synthesis of chiral primary
amines from the corresponding prochiral ketones.[18]
β-Enaminones are vinylogous amides with unique reactivity
and represent important intermediates in the synthesis of a variety
of N-heterocyclic compounds.[1] Specifically, six-membered cyclic
variants have been exploited for the preparation of a diverse array
of bioactive piperidine alkaloids (Figure 1), including pinidinone
and related 2,6-piperidine derivatives,[2] apomitomycin,[3]
There are a number of examples of the application of ATAs
in cascade reactions for the synthesis of nitrogen heterocycles,
starting from readily available or easily accessible dicarbonyl
compounds.[19] We previously reported a novel biocatalytic
disconnection for the regio- and stereoselective synthesis of a
range of 2,6-disubstituted piperidines, relying on a key ω-TA
triggered intramolecular aza-Michael reaction and subsequent
epimerization.[20] To complement the existing literature, we now
report the expansion of the ω-TA-triggered intramolecular aza-
Michael reaction to include ynones as the aza-Michael acceptors
(Scheme 1), affording cyclic β-enaminones in excellent regio- and
stereoselectivity. The products contain a number of functional
handles for further derivatization and represent useful synthetic
building blocks. Additionally, we demonstrate that condensation
mesembrenone,[4]
desoxoprosophylline,[5]
cassine,[6]
deoxyfebrifugine,[7] sedacryptine,[8] selenopsine[9] and the
Coccinellidae defensive alkaloids, including hippodamine.[10]
However, despite their importance, there have been limited
strategies reported for the enantioselective construction of chiral
β-enaminones. Traditional approaches for their synthesis rely on
the sulfide contraction methodology originally reported by
Eschenmoser,[11] modified Knoevenagel-type reactions on
(alkylthio)alkylideniminium salts,[12] lactam-derived iminium
chlorides[13] or related compounds.[14] Alternatively, the direct
condensation of chiral lactim ethers with keto esters followed by
decarboxylation with boric acid represents a useful approach.[15]
More recently, a gold catalyzed cyclisation of N-Boc-6-alkynyl-
3,4-dihydro-2H-pyridines was shown to provide a facile route.[16]
Enzymes represent valuable catalysts for the synthesis of
chiral compounds that are challenging to access using more
N
O
N
N
n-C11H23
N
H
H
O
(-)-solenopsine A
Key building
block
(±)-deoxyfebrifugine
R
H
H
HO
R
N
[a]
[b]
[c]
F. Taday, Dr J. Ryan, Dr E. O’Reilly
School of Chemistry, University of Nottingham, University Park,
Nottingham, NG7 2RD (UK)
E-mail: james.ryan2@ucd.ie
Dr. B. Maciá, Dr V. Caprio
Faculty of Science & Engineering, Division of Chemistry &
Environmental Science, Manchester Metropolitan University,
Chester Street, Manchester M1 5GD (UK)
Dr E. O’Reilly (current address)
School of Chemistry, University College Dublin, Belfield, Dublin 4,
(Ireland)
N
H
H
O
R
N
H
(CH2)10COCH3
β-enaminone
(-)-cassine
(-)-hippodamine
OH
Ph
HO
HO
OH
N
N
(CH2)11CH3
H
N
H
(-)-sedacryptine
(+)-desoxoprosophylline
O
(-)-pinidinone
E-mail: elaine.oreilly@ucd.ie
Figure 1. A selection of natural products that can be made from key b-
Supporting information for this article is given via a link at the end
of the document.
enaminone building blocks.
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10.1002/chem.202000067
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COMMUNICATION
of these enzyme-derived enaminones with various [3+3]
and/or remove the co-product in-situ.[18,19,20] However, the strong
thermodynamic driving force associated with the intramolecular
aza-Michael reaction effectively displaces the reaction equilibrium
towards product formation, necessitating the use of only two
equivalents of isopropylamine. b-Enaminones 1a-g were isolated
in the cis-configuration, presumably due to the added stability of
the intramolecular hydrogen bond between the amine and
carbonyl formation, consistent with previous reports.[2,6,16]
acceptors
enables
the
straightforward
synthesis
of
hexahydroquinoline (HHQ) and tetrahydroquinoline (THQ)
derivatives.
Spontaneous
aza-Michael
reaction
O
O
Selective
transamination
R
R
N
O
NH2
H
O
R
2
1
During the purification of (S)-1d, a minor product was
isolated, characterized and determined to be the carbo-[3+3]
annulation product 3, arising from the reaction of the β-enaminone
1d with unreacted ketoynone 2d (Scheme 3). Although this
compound was only isolated as a minor component (<10% yield),
we postulated that the reaction could be biased towards the
formation of the annulation product, if the enzymatic
transformation could be slowed down sufficiently to allow the
annulation reaction to occur. Adjusting the amine donor
equivalents from 2 to 1 was enough to allow the condensation
reaction to predominate, enabling the isolation of 3 in 78% yield
(Scheme 3). Trace amounts of annulation product was also
observed in a number of the biotransformations to produce 2a-g,
but these compounds were not isolated and characterised. It is
likely that the formation of these side products could also be
enhanced by lowering the equivalents of amine donor.
Scheme 1. A retrosynthetic approach for the synthesis of chiral cyclic β-
enaminones starting from prochiral ketoynones.
Ketoynone substrates 2a-g were prepared via epoxidation
of commercially available 3-methyl-2-cyclohexanone, followed by
Eschenmoser fragmentation (Scheme 2). Subsequent acetal
protection and acylation of the alkyne with the appropriate reagent
provided the substrates after acidic work-up (see ESI for details).
O
O
OH
TsOH,
H2O2,
5 N NaOH,
HO
p-TsNHNH2,
O
O
MeOH
96 %
CH2Cl2, AcOH
49 %
Dean-Stark
63 %
I-1
I-2
1) n-BuLi, THF, -78oC,
O
O
R
R
X
O
O
Table 1. Conversion of ketoynones 2a-g to the corresponding
cyclic β-enaminones using commercially available transaminases.
(X = Cl or I-4: N(Me)OMe)
O
I-3
2) aq. HCl, Et2O
2a-g
O
2d R = Ph (86 %)
2a R = Me (79 %)
2b R = tBu (44 %)
2c R = EtO (71 %)
Commercially
available ATA
R
2e R = p-MeOPh (89 %)
2f R = p-N(Me)2Ph (58 %)
2g R = p-NO2Ph (26 %)
N
O
*
H
O
R
O
NH2
(R)- or (S)-1a-g
2a-g
Scheme 2. Synthesis of 2a-g starting from 3-methyl-2-cyclohexanone.
2 eq.
Initially, four commercially available ATAs were screened for
activity against 2a-d, by employing previously optimized
conditions.[20] To allow access to both enantiomers of 1, two (R)-
selective (ATA117 and ATA025) and two (S)-selective variants
(ATA113 and ATA256) were screened. These enzymes have
been developed by Codexis and represent some of the most
widely utilized commercially available ATAs.[21] This initial screen
showed that ATA025, ATA256 and ATA113 showed the most
promising activity (data not shown) and these enzymes were
therefore selected for preparative-scale reactions (Table 1).
ATA025 achieved excellent conversions with all ketoynones
(88-99%, entries 1, 3, 5, 7, 9 and 13), with the exception of the
dimethylamine derivative 2f (entry 11), where 46% conversion to
the b-enaminone was observed. (S)-selective ATA256 provided
the highest conversions (95-97%) for non-aromatic substrates 2a-
c and the electron deficient aromatic derivative 2g at 40 mM
substrate concentration (entries 2, 4, 6 and 14). The highest
conversions with ketoynone substrates 2d, 2e, 2f were achieved
with (S)-ATA113 (53-92%, entries 8, 10 and 12). In all cases, the
reactions proceeded in good to excellent enantiomeric excess
(83->99%).
Entry
Substrate
R-
ATA
Conv
%
yield
(%)d
e.e
substituent
>99e (R)
>99e (S)
94e(R)
98e (S)
83e(R)
>99e (S)
97e(R)
>99e(S)
94f (R)
98f (S)
1
2
3
4
2a
2a
2b
2b
Me
Me
tBu
tBu
025
256
025
256
91b
95b
>99b
97b
78
43
54
95
5
6
2c
2c
2d
2d
2e
2e
2f
OEt
OEt
025
256
025
113
025
113
025
113
025
256
92b
96b
88b
91b
88c
92c
46c
53c
98c
94c
73
60
72
85
79
52
43
29
58
53
7
Ph
8
Ph
9
p-MeOPh
p-MeOPh
p-N(Me)2Ph
p-N(Me)2Ph
p-NO2Ph
p-NO2Ph
10
11
12
13
14
>99f (R)
98f (S)
>99f (R)
97f (S)
2f
2g
2g
(a) Reaction conditions: ω-TA (5 mg/mL), substrate (40 mM), isopropyl amine
(80 mM), DMSO (10%), pyridoxyl-5’-phosphate (PLP, 1 mM), HEPES buffer (5
mL, 100 mM, pH 7.5), 30 °C, 200 rpm, 24 h. (b) Conversion determined by GC-
FID. (c) Conversion determined by 1H NMR. (d) Isolated yield after flash
chromatography. (e) e.e determined by GC-FID using a chiral column. (f) e.e
determined by HPLC using a chiral column.
The challenging equilibrium typically associated with
transaminase-mediated reactions means that in order to achieve
high conversions to the desired amine product, it is often
necessary to use extremely high equivalents of the amine donor
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yield) and 5b (39% yield) (Scheme 5A), via a carbo-[3+3]
annulation. Subsequently, 5b was crystallised to determine the
overall conformation, as 2D-NMR experiments were inconclusive.
Ph
carbo-[3+3]
annulation with
unreacted 2d
O
O
Ph
ATA113
NH2
1 or 2 eq.
N
A) carbo-[3+3] annulation
N
O
H
H
O
O
Ph
O
O
3
Ph
2d
1d
+
i
N
H
N
H
Equivalents
of 2d
Amine donor
equivalents
Yield of 3 (%)
O
O
1a
4
<10
78
(2S,7R)-5a, 53% yield
1
1
2
1
Scheme 3. Carbo-[3+3] annulation product 3, observed as a side product
(<10%) during the reaction of 2d with the commercial ATAs. Adjusting the
equivalents of amine donor from 2 to 1 allowed the isolation of 3 in 78% yield.
N
H
O
Crystal structure
(2S,7S)-5b, 39% yield
of 5b
B) aza-[3+3] annulation
To demonstrate the potential scope of this novel, one-pot
ATA-annulation cascade, we explored its feasibility for the
synthesis of HHQ derivatives arising from the condensation of β-
enaminones 1 with an alternative ketoynone. Partner 2h, bearing
a phenyl substituent on both carbonyls, was selected to
investigate this crossed condensation (Scheme 4). Wild-type
ATAs typically accept ketone substrates where at least one of the
substituents is ‘small’ (e.g. methyl or ethyl), due to the nature of
their active site pocket. While the properties of the commercial
enzymes (ATA113, ATA256, ATA025) have been optimised,
these catalysts have not been engineered to accept substrates
with two bulky substituents. This means that diphenyl ynone 2h
will not readily undergo transamination in the presence of the
commercial enzymes, which simplifies a one-pot ATA-annulation
cascade, ensuring only a single annulation product is isolated. As
2h is not a substrate for the enzyme, there was no requirement to
limit the equivalents of amine donor and therefore 2 equivalents
were employed. The one-pot transamination of 2c followed by
carbo-[3+3] annulation with 2h proceeded extremely efficiently,
affording the target product 3c in 90% yield after 24 hours
(Scheme 4). Selective transamination of 2d in the presence of 2h
afforded 3d in only 10% yield after 24 hours. This is somewhat
surprising, given that 2d is efficiently converted to 1d in the
absence of 2h (Table 1, entry 7). The one-pot cascade with 2e
also proceeded quite poorly, allowing the isolation of 3e in 27%
yield. It is likely that these reactions can be improved with further
optimisation, but this was not carried out in this study.
O
O
ii
N
H
+
N
Cl
O
O
6
1d
7, 52% yield, 3:1 d.r.
Scheme 5. Annulation reactions of 1a and 1d. A) Carbo-[3+3] annulation: i)
piperidinium acetate, sodium sulfate, EtOAc:Tol (2:3), 100 oC, 16 h. Crystal
structure of 5b (CCDC 1945711). B) Aza-[3+3] annulation: ii) acryloyl chloride,
THF, Δ, 16 h.
The rather low crude d.r (57:43) observed for 5 can be explained
by the formation of a relatively flat hexadiene with a subsequent
lack of axial/equatorial bias affecting stereofacial selectivity. The
aza-[3+3] annulation of 1d with acryloyl chloride 6 provided
lactam 7 in a 52% yield and a 3:1 d.r. (Scheme 5B).
In conclusion, we have expanded the scope of the ω-TA
triggered intramolecular aza-Michael reaction strategy to include
ynone substrates, providing an expedient and general
chemoenzymatic route to valuable chiral cyclic β-enaminone
scaffolds in good yield and enantiomeric excess. This
methodology relies on the exceptional levels of regio- and
stereoselectivity associated with the biocatalytic transamination of
prochiral ketoynone substrates. To highlight the utility of these
functionalisable compounds (1a-e) en route to stereodefined
scaffolds of potential synthetic and medicinal interest, a novel,
one pot tandem TA/aza-Michael/condensation cascade was
developed,
allowing
access
to
polyfunctionalised
hexahydroquinolines 3. Two variations of annulation reactions
were also successfully conducted, providing hexahydroquinolines
5 and quinolizidines 7.
O
Ph
Carbo-[3+3]
annulation
Ph
O
O
2c, 2d or 2e
+
ATA025
NH2
2 eq.
N
Ph
Acknowledgements
1 eq.
H
Ph
O
O
3
R
2h
2 eq.
Research leading to these results has received funding from the
(EPSRC). The UK Catalysis Hub is kindly thanked for resources
and support provided via our membership of the UK Catalysis Hub
Consortium and funded by (EPSRC) (grants EP/K014706/2,
3c, R = OEt, 90% yield
3d, R = Ph, 10% yield
3e, R = p-OMePh, 27% yield
Scheme 4. ATA/Carbo-[3+3] annulation cascade of 2c, 2d, or 2e with 2h in the
presence of 2 equivalents of isopropylamine, affording 3.
EP/K014668/1,
EP/K014854/1,
EP/K014714/1
and
EP/M013219/1). We acknowledge the School of Chemistry UoN
for supporting FT.
Additionally, we explored two annulation reactions involving cyclic
β-enaminones 1a and 1d.[22] The methyl-methyl derivative 1a
reacted with cinnamaldehyde 4 in the presence of piperidinium
acetate, to provide the separable THQ diastereomers 5a (53%
Keywords: Biocatalytic cascade• Transaminase • Aza-Michael •
Ketoynone • Annulation
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Freya Taday, James Ryan,* Stephen P.
Argent, Vittorio Caprio, Beatriz Maciá,
Elaine O’Reilly*
A chemoenzymatic cascade has been
developed for the synthesis of
hexahydroquinoline
and
tetrahydroquinoline derivatives, relying
on a key transaminase-mediated aza-
Michael reaction followed by [3+3]
annulation.
Page No. – Page No.
O
Asymmetric Construction of
Alkaloids Employing a Key ω-
Transaminase Cascade
Ph
One-pot
Biocatalytic
R
O
aza-Michael reaction
O
and [3+3]-annulation
O
*
N
Ph
3 examples
up to 90% yield
H
O
R
Ph
O
Ph
14 examples
up to 99% conv.
95% yield
*
N
H
O
R >99% ee
Layout 2:
COMMUNICATION
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