Reoptimization of the Organocatalyzed Double Aldol Domino Process to a Key Enal Intermediate and Its Application to the Total Synthesis of Δ12-Prostaglandin J3

Article abstract of DOI:10.1002/chem.201802498

Re-investigation of the l-proline catalyzed double aldol cascade dimerization of succinaldehyde for the synthesis of a key bicyclic enal intermediate, pertinent in the field of stereoselective prostaglandin synthesis, is reported. The yield of this process has been more than doubled, from 14 % to a 29 % isolated yield on a multi-gram scale (32 % NMR yield), through conducting a detailed study of the reaction solvent, temperature, and concentration, as well as a catalyst screen. The synthetic utility of this enal intermediate has been further demonstrated through the total synthesis of Δ¹²-prostaglandin J₃, a compound with known anti-leukemic properties.

Full text of DOI:10.1002/chem.201802498

A Journal of
Accepted Article
Title: Re-optimization of the Organocatalyzed Double Aldol Domino
Process to a Key Enal Intermediate and its Application to the
Total Synthesis of Δ¹²-Prostaglandin J₃
Authors: Andrejs Pelss, Narasimhulu Gandhamsetty, James Robin
Smith, Damien Mailhol, Mattia Silvi, Andrew Watson, Isabel
Perez-Powell, Sébastien Prévost, Nina Schützenmeister,
Peter Moore, and Varinder Kumar Aggarwal
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To be cited as: Chem. Eur. J. 10.1002/chem.201802498
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10.1002/chem.201802498
Chemistry - A European Journal
COMMUNICATION
Re-optimization of the Organocatalyzed Double Aldol Domino
Process to a Key Enal Intermediate and its Application to the
Total Synthesis of Δ12-Prostaglandin J3
Andrejs Pelss, Narasimhulu Gandhamsetty, James R. Smith, Damien Mailhol, Mattia Silvi, Andrew J.
A. Watson, Isabel Perez-Powell, Sébastien Prévost, Nina Schützenmeister, Peter R. Moore‡ and
Varinder K. Aggarwal*
Dedication ((optional))
Abstract: Re-investigation of the L-proline catalyzed double aldol
cascade dimerization of succinaldehyde for the synthesis of a key
bicyclic enal intermediate, pertinent in the field of stereoselective
prostaglandin synthesis, is reported. The yield of this process has
been more than doubled, from 14% to a 29% isolated yield on a multi-
gram scale (32% NMR yield), through conducting a detailed study of
the reaction solvent, temperature and concentration, as well as a
catalyst screen. The synthetic utility of this enal intermediate has been
further demonstrated through the total synthesis of Δ12-prostaglandin
J3, a compound with known anti-leukemic properties.
its Achilles’ heel is its low yield (caused by the extensive
oligomerization of succinaldehyde under the reaction conditions).
Interest in the chemistry and biology of prostanoids continues
unabated, with as many publications (ca. 600 per year) in the last
decade as during their heydays of the 1970s.[1] Prostaglandins are
an important class of potent lipid mediators that are involved in
the regulation of many biological processes[2] such as
inflammation,[3] pain response,[4] and fever.[5] Consequently, this
class of compounds has found wide-spread use as
pharmaceuticals[6] for the treatment of several diseases including
pulmonary arterial hypertension[7] and glaucoma.[8] We recently
described a dramatically short route to the prostaglandins,
completing the total synthesis of PGF2α in just seven steps
(Scheme 1),[9] and its subsequent application to the concise
synthesis of the related pharmaceutical analogues latanaprost
and bimatoprost,[10] and alfaprostol.[11] The key step in our
syntheses is the double aldol dimerization of succinaldehyde with
proline and dibenzylammonium trifluoroacetate (DBA) as
catalysts to give the bicyclic enal intermediate (1) in high
enantioselectivity (Scheme 1).[12] Whilst this single step converts
a simple starting material into a complex intermediate[13] fully
primed to enable rapid attachment of the two side chains required,
Scheme 1. Previously reported L-proline catalyzed double aldol domino
reaction for the synthesis of a key bicyclic enal intermediate 1 and its application
to the total synthesis of PGF2α (2).
In this paper we describe a full re-investigation of this key step,
which has culminated in an increase in yield from 14%[9a] to a 29%
isolated yield on a multi-gram scale, thereby enabling the enal 1
to be used not just in further, more efficient prostanoid syntheses,
but also as a highly functionalized and useful building block more
generally. Furthermore, we demonstrate its application to the
concise synthesis of Δ12-PGJ3, a prostanoid of considerable
contemporary interest due to its high activity against cancer stem
cells, a class of cells that are notoriously resistant toward
conventional chemical therapies.[14]
The aldol dimerization of succinaldehyde is complex: L-proline
(2%) is added to a 2 M solution of succinaldehyde in Me-THF and
after 24h the mixture is diluted to 1 M and dibenzylammonium
trifluoroacetate (5, 2%) is added. The two catalysts perform
different roles: L-proline catalyzes the first aldol but does not
catalyze the second aldol and 5 catalyzes the second aldol
condensation and does not (and must not) catalyze the first aldol
otherwise the reaction would occur with low enantioselectivity.
The catalysts must be added sequentially since 5 inhibits the first
aldol reaction with proline and the time of addition is important
since reaction of succinaldehyde with L-proline leads to oligomers
over time. Under these conditions, a 14% yield was achieved
(Table 1, entry 1), and so we embarked on a further optimization
program re-investigating all the parameters. A small improvement
[*]
Dr. A. Pelss, Dr. N. Gandhamsetty, Dr. J. R. Smith, Dr. D. Mailhol,
Dr. M. Silvi, Dr. A. J. A. Watson, I. Perez-Powell, Dr. S. Prévost, Dr.
N. Schützenmeister, and Prof. Dr. V. K. Aggarwal,
School of Chemistry, University of Bristol
Cantock’s Close, Bristol, BS8 1TS, U.K.
‡
Dr. P. R. Moore, Pharmaceutical Technology and Development,
AstraZeneca, Silk Road Business Park, Charter Way, Macclesfield
SK10 2NA, U.K.
E-mail: v.aggarwal@bristol.ac.uk
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201802498
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COMMUNICATION
in yield (16%) was achieved by changing the solvent to
strategy, just two extractions enabled full recovery of enal 1, which
was purified by column chromatography – it was essential to pre-
treat the silica gel with water (50 wt%) to ensure efficient removal
of any remaining succinaldehyde and oligomeric material during
chromatography. Using our optimized conditions and improved
work-up and purification, 50 g of succinaldehyde was transformed
into 12.8 g of enal 1 (29% isolated yield) as an inconsequential
4:1 mixture of diastereomers, and with the same enantiomeric
ratio (99:1 er) as previously reported.
acetonitrile (entry 2). The yield was further increased to 19%
Table 1. Re-optimization of the synthesis of enal 1[a]
In order to further exemplify the synthetic utility of the enal 1, we
chose Δ12-prostaglandin J3 (Δ12-PGJ3, 3, Scheme 1) as a target
because of its considerable biological potency towards stem cell
cancer.[14] Nicolaou and co-workers recently reported several
strategies for the total syntheses of Δ12-PGJ3.[16] These strategies
were subsequently applied to the development of a series of even
more potent analogues as potential clinical candidates for stem
cell cancer treatment, making this an even more sought-after
target.[17] We have previously used 1 to form the C12–C13 bond
(prostaglandin numbering) in the syntheses of a variety of
prostanoids through conjugate addition of a nucleophile to the
electrophilic enal moiety (Scheme 2A). We reasoned that by
transforming enal 1 into enamide 7, it would change the reactivity
of the C12-position from electrophilic to nucleophilic, further
broadening the utility of our key enal (Scheme 2A). In order to
construct Δ12-PGJ3, disconnection of the C12–C13 bond through
an aldol/dehydration reaction sequence would require β-boryl
Entry Solvent 2nd Cat. T[°C] t [h] Conc. 1 [M] Conc. 2 [M] Yield [%][b]
1
THF
5
5
RT
RT
RT
RT
65
65
65
65
65
14
20
24
24
2
2.0
2.0
1.0
1.0
2.0
2.0
1.0
0.75
0.75
1.0
1.0
1.0
1.0
2.0
2.0
0.5
0.2
0.35
14
2
MeCN
16
3
MeCN 5[c]
MeCN 6[c]
19 (9)
20 (20)
23
4
5
MeCN
EtOAc
EtOAc
EtOAc
6
6
6
6
6
6
2
21
7
2
28
8[d]
2
33 (31)
32 (29)
9[d,e] EtOAc
2
aldehyde
8 and enone 9 (Scheme 2B). This type of
aldol/dehydration strategy was originally reported by
[a] Reaction conditions (unless otherwise stated): Succinaldehyde
(5.81 mmol), L-proline (2 mol%), solvent (X M), RT; then: 2nd catalyst (2 mol%),
[b] Yield determined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene
as an internal standard (isolated yields following chromatographic purification
are shown in parentheses). [c] 5 mol% of the 2nd catalyst was used. [d] 40 h
reaction time for 1st step. [e] 50 g succinaldehyde (581 mmol) was used.
Kobayashi[18] and has subsequently been applied to the
16c, 17]
syntheses of Δ12-PGJ3 3[16a,
and other closely related
prostaglandins.[19] Boryl aldehyde 8 was selected as a masked
hydroxy aldehyde equivalent since it can be easily prepared by
catalytic
enantioselective
conjugate
borylation,[20]
and
subsequently unmasked later in the synthesis by stereospecific
oxidation of the boronic ester.
(NMR) by reducing the initial concentration to 1 M (entry 3), but
under these reaction conditions, the enal was isolated in only 9%
yield. This disparity between the NMR and isolated yields was a
consequence of the formation of a hemiaminal ether by-product
4, which formed upon addition of catalyst 5 to the lactol moiety of
1 during the isolation process. An extensive screening of the
second catalyst was undertaken, and we found that the formation
of the hemiaminal ether by-product could be avoided using
thiomorpholinium trifluoroacetate 6, resulting in 20% yield (both
NMR and isolated) of the enal 1 (entry 4). Increasing the
temperature of the second step led to an improved 23% yield in
just 2 h (entry 5). An extensive solvent study (see SI for further
examples) revealed that whilst ethyl acetate performed similarly
to acetonitrile (21% vs 23%, entries 5 and 6, respectively), it led
to significantly less oligomerization of succinaldehyde. Reducing
the concentration further in both the first and second phases of
the reaction resulted in further improvements (entries 7 and 8)
culminating in a 33% NMR yield and 31% isolated yield (entry 8).
On scale, isolation was initially problematic. Evaporation followed
by chromatography was ineffective, giving enal 1 contaminated
by both oligomers and succinaldehyde. We were wary of carrying
out an aqueous work-up because we had previously found that
the enal is partially water soluble and required multiple extractions
even from brine solutions, resulting in excessively large volumes
of solvent. However, a recent report highlighting the beneficial
effects of using Na2SO4 to salt-out water soluble compounds
prompted us to reinvestigate aqueous work-ups.[15] Using this
Scheme 2. A) Changing reactivity mode of our bicyclic enal intermediate from
electrophilic to nucleophilic. B) Retrosynthetic analysis of Δ12-PGJ3 3.
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10.1002/chem.201802498
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Scheme 3. Synthetic route to Δ12-PGJ3 (3) from enal 1 and leaf alcohol (19).
Furthermore, it avoids potential elimination of a protected -
alkoxy enone to the dieneone. Enone 9 could be obtained by
olefination of hemiacetal 11, followed by hydrolysis of the
carbamate group and elimination. The carbamate itself could
be derived from carboxylic acid 13.
degassed water and para-toluenesulfonic acid to the reaction
mixture effected the hydrolysis of the enamide group and
dehydration to give enone 16 in 79% yield. The enone acid 16
was subsequently converted into the t-butyl ester 9 in 83%
yield.
The synthesis of Δ12-PGJ3 3 began through a double oxidation
of enal 1 to the lactone-acid 13 using standard Pinnick
oxidation conditions in 74% yield (Scheme 3). Carboxylic acid
13 was initially converted into acyl azide 14 in 80% yield.
Heating 14 in toluene effected a Curtius rearrangement to
afford an intermediate isocyanate, which was trapped with
benzyl alcohol to give carbamate 12 in 90% yield. While it was
possible to obtain 12 directly by adding benzyl alcohol to the
cooled toluene solution, this led to sluggish nucleophilic
capture reactions. It was crucial to remove toluene before
alcohol addition to ensure a high yield of 12. Ene-carbamate
12 was then reduced to hemiacetal 11 with DIBAL-H in 98%
yield. Initially, the Wittig reaction between hemiacetal 11 and
phosphonium salt 10 was problematic due to poor conversion
of 11 and the enamide product 15 was found to be difficult to
isolate perhaps due to its limited stability. After considerable
optimization, it was found that isolation of the enamide 15 could
be avoided by first treating the hemiacetal 11 with excess
phosphonium salt 10 and KOt-Amyl in THF. Direct addition of
The lower side chain was prepared in a three-step process
from leaf alcohol 19 (Scheme 3). Following a known literature
procedure,[21] 19 was converted into α,β-unsaturated ester 20
by initial oxidation to the corresponding alcohol, followed by a
direct Wittig reaction in the same pot. Ester 20 was subjected
to catalytic asymmetric conjugate addition with B2pin2,[20a] to
provide a β-boryl ester in high yield and enantiomeric excess
(85%, 93:7 er). The boronic ester was subsequently reduced
to the required β-boryl aldehyde 8 in 93% yield upon treatment
with DIBAL-H.
To complete the synthesis of Δ12-PGJ3 (3), we commenced the
development of an aldol reaction between enantiomerically
enriched fragments 8 and 9 (Scheme 3). Initially, 1.2
equivalents of LDA were added dropwise to a solution of 8 and
9 at −78 °C to give the expected aldol product 17 as a mixture
of C13-epimers in 23% NMR yield (Scheme 3). Increasing the
loading of LDA to 2.0 equivalents dramatically improved the
reaction to provide 17 in a 75% NMR yield. Due to the
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since it too used succinaldehyde in a double aldol-type (Mannich)
reaction. See: E. J. Sorensen, Nature 2012, 489, 214-215.
[10] S. Prevost, K. Thai, N. Schützenmeister, G. Coulthard, W. Erb, V. K.
Aggarwal, Org. Lett. 2015, 17, 504-507.
[11] H. Baars, M. J. Classen, V. K. Aggarwal, Org. Lett. 2017, 19, 6008-
6011.
instability of β-hydroxy boronic ester 17 towards column
chromatography, the crude reaction mixture from the aldol
reaction was treated with MsCl and NEt3 to give the
corresponding mesylate, and subsequent elimination upon
reaction with DBU produced exclusively the E-configured
elimination product. The resulting boronic ester was oxidized
to secondary alcohol 18 using NaBO3·4H2O in 23% overall
yield (over the three steps from 8 and 9). Finally, treatment with
HBF4 gave Δ12-PGJ3 (3) in a 75% yield. The total synthesis of
Δ12-PGJ3 (3) was achieved in 12 steps (longest linear
sequence, LLS).
[12] (a) For related organocatalytic syntheses of cyclopentanes and their
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synthesis, see: Y. Hayashi, Chem. Sci. 2016, 7, 866-880.
[13] B. Heasley, Curr. Org. Chem. 2014, 18, 641-686.
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C. R. H. Hale, A. ElMarrouni, Chem. Eur. J. 2016, 22, 8559-8570.
[17] K. C. Nicolaou, K. K. Pulukuri, S. Rigol, P. Heretsch, R. Yu, C. I.
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University), WO2015048268 (A1), 2015.
In conclusion, we have significantly improved the yield of our
previously reported L-proline catalyzed double aldol
dimerization of succinaldehyde from 14% to 29% for the
synthesis of a key enal intermediate 1 that can be employed in
the synthesis of a range of prostanoids. This has been
achieved through a thorough re-evaluation of all of the reaction
parameters, which led us to make four key modifications of the
reaction conditions: changing Me-THF for EtOAc, changing
dibenzylammonium trifluoroacetate 5 to thiomorpholinium
trifluoroacetate 6, the temperature of the second step from
25 °C to 65 °C, and the concentration has been decreased
from 2 M to 0.75 M in the first step and from 1 M to 0.35 M in
the second step. The synthesis, and the practical isolation and
purification of enal 1 on a decagram scale has also been
developed. Furthermore, we have exemplified the synthetic
versatility our enal intermediate 1 through its application to the
total synthesis of Δ12-PGJ3 (3). This was achieved through an
umpolung approach involving the conversion of the
electrophilic enal moiety into an ene-carbamate, which serves
as a masked nucleophilic moiety.
Acknowledgements
We thank EPSRC (EP/M012530/1) for support of this work.
I.P.P. thanks AstraZeneca and the Bristol Chemical Synthesis
Centre for Doctoral Training, funded by EPSRC
(EP/G036764/1),
N.
S.
thanks
the
Deutsche
Forschungsgemeinschaft (DFG) and the Marie-Sklodowska-
Curie Fellowship program (EC FP7 623426) for postdoctoral
fellowships.
A.P.
thanks
REGPOT-CT-2013-316149-
InnovaBalt for partial fellowship support. We would like to thank
Ian Davies (Princeton University) for useful discussions
relating to the purification of enal 1.
Keywords: prostaglandins • organocatalysis • total synthesis
• aldol reaction • Δ12-PGJ3
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[9]
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10.1002/chem.201802498
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
A. Pelss, N. Gandhamsetty, J. R. Smith,
D. Mailhol, M. Silvi, A. J. A. Watson, I.
Perez-Powell, S. Prévost, N.
Schützenmeister, P. R. Moore and V. K.
Aggarwal*
Page No. – Page No.
Text for Table of Contents
Re-optimization of the
Organocatalyzed Double Aldol
Domino Process to a Key Enal
Intermediate and its Application to
the Total Synthesis of Δ12-
Prostaglandin J3
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