Total Synthesis of a Docosahexaenoic Acid Prostanoid Using an Intramolecular Organocatalytic Michael Reaction of a Formyl-Enal Derivative

Article abstract of DOI:10.1021/acs.orglett.0c02553

The total synthesis of a docosahexaenoic-acid-derived prostaglandin, 4,11-diepi-4-F4t-neuroprostane, featuring a complex lateral chain was achieved for the first time. A novel prostaglandin cyclopentane skeleton obtained via an intramolecular highly selective organocatalytic Michael sequence of a formyl-enal derivative allowed the desired and exclusive thermodynamic trans configuration of the lipidic lateral chains.

Full text of DOI:10.1021/acs.orglett.0c02553

pubs.acs.org/OrgLett
Letter
Total Synthesis of a Docosahexaenoic Acid Prostanoid Using an
Intramolecular Organocatalytic Michael Reaction of a Formyl-Enal
Derivative
́
́
Johanna Revol-Cavalier, Valerie Bultel-Ponce, Alexandre Guy, Thierry Durand, Camille Oger,*
and Jean-Marie Galano*
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ABSTRACT: The total synthesis of a docosahexaenoic-acid-derived prostaglandin, 4,11-diepi-4-F4t-neuroprostane, featuring a
complex lateral chain was achieved for the first time. A novel prostaglandin cyclopentane skeleton obtained via an intramolecular
highly selective organocatalytic Michael sequence of a formyl-enal derivative allowed the desired and exclusive thermodynamic trans
configuration of the lipidic lateral chains.
and a potential unique drug for ventilator-induced diaphrag-
rostaglandins (PGs) remain a souvenir of organic
Pchemists, being forever embedded in the art of total matic dysfunction (VIDD).11 Thus because DHA PGs were
synthesis thanks to the pioneering work of E. J. Corey1 and
never investigated nor synthesized in the past, this prompted
many other great chemists.2 For biochemists and biologists,
us to synthesize one 4-F4t-NeuroP counterparts, the 4,11-diepi-
4-F4t-neuroprostane 1, to further evaluate the biological and
analytical relevancies of unstudied PGs. Recent synthetic
efforts in the synthesis of PG revealed the pertinent use of
organocatalysis to construct advanced five-membered ring
prostanoid skeleton intermediates. Aggarwal and coworkers
developed a one-flask access to a key bicyclic enal intermediate
ready for lateral chain introduction by the 1,4 addition of vinyl-
cuprates or copper acetylide derivatives and Wittig reactions.12
Hayashi and coworkers also reported powerful organocatalytic
cascade sequences for PG core skeletons,13 even to the point of
establishing one side chain in the process.14 Novel synthetic
methodologies were also applied for side-chain introduction,
such as Baran decarboxylative alkenylation with an organozinc-
derived olefin for both vinyl and allyl side chains in a recent
the same holds true, as PGs remain the most studied
oxygenated polyunsaturated fatty acid (PUFA) metabolites.3
The PGs fulfill a considerable number of research fields due to
their original biosynthesis by cyclooxygenase enzymes
(COXs),4 their biological actions as hormone-like com-
pounds,5 their use as biomarkers of human diseases, and,
finally, their therapeutic applications as drugs (synthetically
modified or not) for human or animals.6
In 1990 Morrow and coworkers discovered that autoxidation
of phospholipidic arachidonic acid can also generate racemic
PGF2α together with its C8 isomer named 15-F2t-isoprostane
(Figure 1a).7,8 Docosahexaenoic acid (DHA) also autoxidizes
into isoprostane structures (named neuroprostanes) and PGs,
whereas interestingly, no known enzyme can produce PGs
from DHA.9 Our group recently codiscovered the potent
biological activity of 4-F4t-neuroprostane (4-F4t-NeuroP), a
DHA-derived isoprostane (Figure 1b) that protects the in vitro
and in vivo post-translational modifications of the ryanodine
receptor under oxidative conditions.10
Received: July 31, 2020
This unprecedented biological activity for an organic
compound makes it a formidable antiarrhythmic compound
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Org. Lett. XXXX, XXX, XXX−XXX
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intermediate for our synthesis. This useful intermediate
would arise from the formyl enal system B following a rare
organocatalytic intramolecular Michael addition.18−20 An
asymmetric aldol reaction between synthons C and D should
provide the requisite 1,3-hydroxy unit.21
Our endeavor started with the synthesis of the dimethyla-
cetal of fumaraldehyde 2,22 following an inexpensive slightly
modified protocol, from dimethoxyfuran in two steps on a
large scale (51% yield) (Scheme 2).23 Implementation of the
Scheme 2. Asymmetric Synthesis of Formyl-Enal Derivative
6
Figure 1. (a) PGF2α and its C8 epimer (15-F2t-IsoP). (b) Structures
of 4-F4t-neuroprostane and 4,11-diepi-4-F4t-neuroprostane (1). By
definition, the α chain in PGs has to be presented on top.
synthesis of PGF2α.15 Stereoretentive cross-metathesis also
proved successful for prostanoid synthesis to introduce Z-
alkene side chains with excellent geometric control.16
However, one particular feature of PGs derived from
complex PUFAs (e.g., DHA) compared with the well-known
PGF2α is the inherent sensitivity of skipped diene units (ω-
chain in 1) (Scheme 1). Precursors of such side chains cannot
Scheme 1. Retrosynthesis of 4,11-diepi-4-F4t-NeuroP 1
1,3-oxygenation pattern relies on an asymmetric vinyloguous
Mukaiyama reaction.21 We previously observed that the use of
another dienolate partner than Chan’s diene 3 proved to be
problematic at the cleavage of the 1,3-dioxin-4-one-derivative;
therefore, we turned to the Ramesh protocol24 using the chiral
titanium(IV)−1,1′-binaphtho complex (20% loading) followed
by TBAF deprotection of the trimethylsilyl ether to give the
requisite δ-hydroxy-β-ketoester 4 in 58% yield (over two steps)
with 92% ee.23 Diethyl methoxyborane treatment followed by
the successive addition of sodium borohydride at −78 °C
provided the syn-diol 5 in 89% yield with high selectivity (de =
90%).25
The protection of the alcohols as their TBS-ethers was
followed by the chemoselective DIBAL-H reduction of the
carboxylic ester moiety prior to the acetal deprotection, which
relieves the formyl-enal Michael substrate 6 and permits the
chromatographic removal of the undesired anti-isomer in 60%
yield over three steps.
The intramolecular organocatalyzed Michael addition
investigations are described in Table 1, and because the
resulting bis-aldehyde could be instable, the crude reaction
mixture was treated with NaBH4 to isolate the corresponding
diol. The intramolecular C−C bond formation of formyl-enal
derivatives was originally demonstrated with the stoichiometric
use of achiral or chiral amines by the Schreiber group in
1986.18 Later, List and coworkers described an enantioselective
organocatalytic version on a naked substrate.19 Finally, the
MacMillan group showed diastereoselective modulation
depending on the solvent and enantiomer of the organocatalyst
used.20
accommodate cuprate or organozinc preparation, and cross-
metathesis with an advanced acyclic 1,4-diene precursor
cannot be accomplished without the formation of the favored
1,4-cyclohexadiene product. The Corey lactone, famously
known for PG synthesis, could seem ideally suited for 1;
however, its lactone functionality may temper this idea. Indeed,
the Wittig reaction conditions for the skipped diene unit of 1
are not compatible with such a lactol unit (lactol-aldehyde
equilibrium not favored) because of the very low temperature
required for this sensitive phosphonium-ylide reagent. The
alternative would be a four-step sequence to convert the
protected lactol and release the aldehyde functionality. This
conundrum was observed and solved during our effort in the
synthesis of 4-F4t-NeuroP (epimer of 1)17a with the help of a
1,5-pentadiol unit such as A (albeit with a 1,2-cis
configuration) together with a novel regioselective enzymatic
monoprotection.17b Structure A can thus be the perfect
B
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catalysts, such as trifluoromethyl-substituted diarylprolinol 9 or
TMS-derived 10 (both enantiomers) in THF, gave only the
recovered starting material (Table 1, entries 12 and 13).
Similarly, the achiral N-methyl aniline (PhNHMe) reagent
used in Schreiber’s protocol18 gave no conversion (Table 1,
entry 14). The efficiency of both enantiomers of proline and
the poor results of other catalysts led us to consider the
possibility of an acid-catalyzed mechanism, but the use of
trifluoroacetic acid resulted in no conversion (Table 1, entry
15).
Table 1. Effect of the Catalyst and the Solvent in the
Organocatalyzed Michael Addition
The configuration of compound 7 was assigned as a
(1S,2R)-trans isomer thanks to NOESY experiments on its
corresponding lactone and comparisons with two other known
diastereoisomers of 7.23 The above results showed the
difficulty in predicting the diastereomeric outcome of this
intramolecular reaction, as we observed that compound 6
overcomes the possible chiral catalyst influence, leading to the
thermodynamic stable 1,2-trans adduct encountered in the PG
skeleton when MacMillan and Mangion substrate showed L-
and D-proline reversed stereoinductive effects.20 Moreover, the
reaction may proceed through an iminium-enol, enamine-enal,
or even a dual mechanism via open- or close-state transition
states, and further investigations (experimental reactions and
computational molecular modeling) are ongoing.
Quite surprisingly, and to the best of our knowledge, diol 7
was never considered for PG synthesis, but with this useful
skeleton in hand, the first synthesis of 4,11-diepi-4-F4t-NeuroP
1 continued.
First, the selective enzymatic acetylation of 1,5-nonsy-
metrical diols developed by our group proved once again to
be effective, and diol 7 was regioselectively acetylated at the
less hindered alcohol (Scheme 3) with complete selectivity.17b
Dess−Martin oxidation of the remaining alcohol afforded the
aldehyde substrate, which was directly coupled to the anion of
phosphonate 1117a introducing the backbone of the α-chain of
12 in 52% yield over three steps. The remaining functionaliza-
a
entry
catalyst
8 or ent-8
L-proline
solvent
results and isolated yield(s) of 7
1
2
3
4
5
6
7
8
CHCl3
CHCl3
CHCl3
DMSO
CH3CN
MeOH
i-Pr2O
MTBE
Et2O
THF
THF
THF
THF
degradation
b
(34, 34 )
b
D-proline
(36, 34 )
b
L-proline
(27, 28 )
b
L-proline
(32, 30 )
b
L-proline
(16, 18 )
L-proline
(38)
(42)
(51)
L-proline
9
L-proline
c
b
10
11
12
13
14
15
L-proline
(55, ,42 )
cd
,
L-proline
(56 )
9 or ent-9
10 or ent-10
PhNHMe
trifluoroacetic acid
reduced SM
reduced SM
reduced SM
reduced SM
CHCl3
THF
a
Unless otherwise noted, the reaction was performed by employing 6
(0.13 mmol) and the organocatalyst (0.04 mmol, 30 mol %) in
solvent (3 mL) at room temperature for 16 h. No full conversion was
observed. The aldol product mixture was treated with NaBH4 (0.39
mmol), and the diol was characterized. See the Supporting
Information for details. 4 h reaction time, no full conversion, Full
conversion after 16h. On a 1 g (2.5 mmol) scale at room
b
c
d
temperature for 16h.
Scheme 3. Synthesis of 4,11-diepi-4-F4t-NeuroP 1
List’s protocol that described the almost exclusive 1,2-trans
configuration of the corresponding Michael reaction adduct19
gave a complete degradation of the starting material 6 with
imidazolidinone catalyst 8 or its enantiomer after 4 h (Table 1,
entry 1). MacMillan’s L-proline thermodynamic control
20
protocol in CHCl3 exclusively provided the requisite trans
isomer 7 as the sole observable isomer (out of the four possible
ones) in 34% yield (no full conversion after 4 or 16 h, Table 1,
entry 2). Interestingly, D-proline as a catalyst afforded the same
stereoisomer in a similar yield (Table 1, entry 3). Solvent
screening with L-proline as the catalyst showed that highly
polar solvents used by MacMillan for kinetic control (MeOH,
CH3CN, and DMSO; Table 1, entries 4−6) resulted in lower
yields still with total 1,2-trans selectivity. Ether solvents proved
to be more satisfactory (Table 1, entries 7−10), as the best
result was observed with Et2O and THF (Table 1, entries 9
and 10), and only THF afforded full conversion. The gram-
scale investigation afforded 7 with the same yield and reaction
time (56%, 16 h) (Table 1, entry 11). Possible enantiomeric
enrichment during the L-proline-catalyzed Michael addition
was checked by performing the reaction starting from ent-6
with both L- and D-proline. ent-7 was obtained with the same
isolated yields (after 16 h), suggesting that no ee enrichment
occurred. (This strategy was used because the ee values of 7 or
other derivatives could not be obtained.) Other screened
C
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Letter
́ ́
́
Valerie Bultel-Ponce − Institut des Biomolecules Max
tion to access intermediate 13 required the diastereomeric
reduction of the enone 12. Thus the (S)-CBS-2-methylox-
azaborolidine strategy provided the (R)-alcohol product with
good selectivity (dr = 88:12 by 1H NMR) and was followed by
TBS-ether protection in good yield (74% over two steps). The
acetate cleavage of 13 under basic conditions (K2CO3 in
MeOH) allowed the chromatographic removal of the
undesired C4-(S)-epimer. Dess−Martin oxidation and the
subsequent ω-chain introduction by a Wittig procedure with
the previously described complex ylide of phosphonium salt
1426 provide 15 in 48% yield over three steps. Finally, tetra-n-
butylammonium fluoride (TBAF)-mediated cleavage of the
TBS groups led to the corresponding five-membered lactone,
which was ring-opened with LiOH to provide 4,11-diepi-4-F4t-
NeuroP 1 in 53% over two steps.
́
Mousseron UMR 5247, CNRS, ENSCM, Universite de
Montpellier, Montpellier 34093 Cedex 05, France
́
Alexandre Guy − Institut des Biomolecules Max Mousseron
́
UMR 5247, CNRS, ENSCM, Universite de Montpellier,
Montpellier 34093 Cedex 05, France
́
Thierry Durand − Institut des Biomolecules Max Mousseron
́
UMR 5247, CNRS, ENSCM, Universite de Montpellier,
Montpellier 34093 Cedex 05, France
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02553
Notes
The authors declare no competing financial interest.
Our results demonstrated the pertinence of the described
organocatalytic disconnection to provide an ideally adapted
Corey lactone surrogate for complex PGs in seven steps. Our
approach was validated by the first total synthesis of a PG
DHA-derived isomer 1, named 4,11-diepi-4-F4t-NeuroP,
according to the isoprostane nomenclature in 17 steps from
2 and 3 in 1.6% overall yield.
ACKNOWLEDGMENTS
■
We acknowledge the University of Montpellier (doctoral
fellowship of J. R.-C.) and the CNRS. We thank Aurelien
Lebrun from the Laboratoire de Mesure Physique for the
NOESY experiments.
́
Further perspectives include the development of a cascade
process, as one could envisage that the known 4-hydroxy-2,6-
octadienedial27 would accommodate a regioselective organo-
catalytic oxa-Michael addition28 (Jørgensen catalyst) to
introduce the 1,3-syn diol unit followed by subsequent
intramolecular cyclization (this work) to furnish a similar PG
skeleton (and orthogonal protection of the 1,3-diol). Recent
investigations on catalytic intramolecular conjugate additions
of aldehyde-derived enamines to α,β-unsaturated esters could
also promise an alternative approach to the above one-pot
process where no regioselective oxa-Michael reaction would be
required.29
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AUTHOR INFORMATION
■
Corresponding Authors
́
Camille Oger − Institut des Biomolecules Max Mousseron UMR
5247, CNRS, ENSCM, Universite de Montpellier, Montpellier
34093 Cedex 05, France; orcid.org/0000-0002-5177-
5792; Email: camille.oger@umontpellier.fr
Jean-Marie Galano − Institut des Biomolecules Max Mousseron
UMR 5247, CNRS, ENSCM, Universite de Montpellier,
Montpellier 34093 Cedex 05, France; orcid.org/0000-
0001-6412-4967; Email: jean-marie.galano@umontpellier.fr
́
́
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Johanna Revol-Cavalier − Institut des Biomolecules Max
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