Catalyst Repurposing Sequential Catalysis by Harnessing Regenerated Prolinamide Organocatalysts as Transfer Hydrogenation Ligands

Article abstract of DOI:10.1021/acs.orglett.9b04033

A catalyst repurposing strategy based on a sequential aldol addition and transfer hydrogenation giving access to enantiomerically enriched α-hydroxy-γ-butyrolactones is described. The combination of a stereoselective, organocatalytic step, followed by an efficient catalytic aldehyde reduction induces an ensuing lactonization to provide enantioenriched butyrolactones from readily available starting materials. By capitalizing from the capacity of prolineamides to act as both an organocatalyst and a transfer hydrogenation ligand, catalyst repurposing allowed the development of an operationally simple, economic, and efficient sequential catalysis approach.

Full text of DOI:10.1021/acs.orglett.9b04033

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Catalyst Repurposing Sequential Catalysis by Harnessing
Regenerated Prolinamide Organocatalysts as Transfer
Hydrogenation Ligands
Frederic Bourgeois,† Jonathan A. Medlock,‡ Werner Bonrath,‡ and Christof Sparr*,†
†Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland
‡DSM Nutritional Products Ltd., P.O. Box 2676, 4002 Basel, Switzerland
S
* Supporting Information
ABSTRACT: A catalyst repurposing strategy based on a sequential
aldol addition and transfer hydrogenation giving access to
enantiomerically enriched α-hydroxy-γ-butyrolactones is described.
The combination of a stereoselective, organocatalytic step, followed
by an efficient catalytic aldehyde reduction induces an ensuing
lactonization to provide enantioenriched butyrolactones from readily
available starting materials. By capitalizing from the capacity of
prolineamides to act as both an organocatalyst and a transfer
hydrogenation ligand, catalyst repurposing allowed the development
of an operationally simple, economic, and efficient sequential
catalysis approach.
he combination of multiple distinct catalytic trans-
Scheme 1. Schematic Overview of Catalyst Repurposing
Sequential Catalysis (CRSC)
Tformations in a one-pot reaction procedure enables cost-
and time-efficient processes toward complex targets from readily
available starting materials. In particular, the interplay between
organocatalysis and transition-metal catalysis can provide
unique possibilities for the formation of valuable organic
frameworks.1 In relay, tandem, or cascade catalysis, a common
intermediate is released from the first catalytic cycle that directly
enters a second one. This requires high reagent compatibility,
which can often be circumvented by a sequential catalysis
approach where after the completion of the first catalytic event,
reagents or catalysts required for the second transformation are
added. This permits an increased scope and allows more
variation of reaction conditions.2
Because amines,3 N-heterocyclic carbenes (NHCs),4 and
phosphines5 are frequently used as both organocatalysts and
ligands, we became intrigued by the prospects of a repurposing
strategy where the first catalyst upon regeneration is converted
into the second by the addition of a metal precatalyst
(Scheme 1a). This in situ catalyst repurposing sequential
catalysis strategy (CRSC) would thus constitute a particularly
effective method for a wide range of transformations. We
recognized prolineamides as an ideal compound class for CRSC
because they have been successfully used as organocatalysts in
stereoselective cross-aldol reactions6 and as ligands in transfer
hydrogenations.7 We hence envisioned to exploit the proline
amide derivatives in CRSC for the stereoselective synthesis of
α‑hydroxy-γ-butyrolactones 1, first as catalyst of a stereo-
selective aldol addition to intermediate 2 and, after repurposing,
as ligand to promote the aldehyde reduction that induces a
lactonization (Scheme 1b).
Received: November 11, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04033
Org. Lett. XXXX, XXX, XXX−XXX

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions for Catalyst Repurposing Sequential Catalysis
b
entry
catalyst/ligand
(RuCl2(p-cymene))2 (mol %)
t (h)
conv. (%)
e.r.
1
2
3
4
5
6
7
8
9
3, 10 mol %
4, 10 mol %
5, 10 mol %
6, 10 mol %
7, 10 mol %
8, 20 mol %
9, 10 mol %
10, 10 mol %
11, 5.0 mol %
2.5 mol %
2.5 mol %
2.5 mol %
2.5 mol %
2.5 mol %
2.5 mol %
1.0 mol %
1.0 mol %
1.0 mol %
18
−
−
18
18
18
18
2
99
−
−
99
99
99
99
99
99
82:18
−
−
79:21
85:15
84:16
85:15
19:81
86:14
4
a
Reaction conditions: isobutanal (0.40 mmol), ethyl glyoxalate (0.40 mmol, 47 wt % in toluene), organocatalyst (5.0−20 mol %), t-BuOH
b
(0.4 mL), 25 °C, 24−48 h, TM precursor (1.0−2.5 mol %), sodium formate (2.00 mmol), water (1 mL), 25 °C, 2−18 h. Determined by GC
based on consumed starting material and product formation.
a
Table 2. Effect of Transition-Metal Precursors
b
entry
precursor
precursor loading
T (°C)
t (h)
conv. (%)
1
2
3
4
5
6
7
8
9
(RuCl2(p-cymene))2
(RuCl2(p-cymene))2
(RuCl2(p-cymene))2
(RuCl2(benzene))2
(RhCl2Cp*)2
(IrCl2Cp*)2
(IrCl2Cp*)2
(IrCl2Cp*)2
(IrCl2Cp*)2
0.50 mol %
0.50 mol %
0.50 mol %
0.50 mol %
0.50 mol %
0.50 mol %
0.50 mol %
0.25 mol %
0.10 mol %
rt
26
6
1
5
2.5
1
4
2
5
98
98
94
92
97
99
99
93
99
40
60
40
40
40
rt
40
40
a
Reaction conditions: isobutanal (0.40 mmol), ethyl glyoxalate (0.40 mmol, 47 wt % in toluene), organocatalyst (5.0 mol %), t-BuOH (0.4 mL),
b
25−60 °C, 18 h, TM precursor (0.1−0.5 mol %), sodium formate (2.00 mmol), water (1 mL), 25 °C, 1−26 h. Determined by GC based on
consumed starting material and product formation.
Enantioenriched α-hydroxy-γ-butyrolactones 1 are key
industrial intermediates,8 chiral auxiliaries,9 and building blocks
for the synthesis of biologically active compounds and natural
products.10 Their previous preparation typically involved
resolution protocols8,11 or a stepwise stereoselective catalysis
strategy.12 Interestingly, (R)-pantolactone 1a (R = Me), the key
intermediate for the synthesis of vitamin B5 (pantothenic acid),
was prepared by a one-pot combination of organo- and
13
̈
biocatalysts by Groger, Berkessel, and coworkers. We thus
initiated our catalyst repurposing study by preparing (R)‑pan-
tolactone 1a using the regenerated amine catalyst as a ligand for
a transfer hydrogenation. To identify catalysts, solvents,
additives, and conditions suitable for both steps in the sequence,
we first individually evaluated their effect on the stereoselectivity
B
DOI: 10.1021/acs.orglett.9b04033
Org. Lett. XXXX, XXX, XXX−XXX

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Organic Letters
Letter
a
Table 3. Scope and Limitations of the Catalyst Repurposing Sequential Catalysis for α-Hydroxy-γ-butyrolactones
a
Reaction conditions: aldehyde (1.00 mmol), ethyl glyoxalate (1.00 mmol, 47 wt % in toluene), 11 (5.0−10 mol %), t-BuOH (1.0 mL), 25 °C,
b
c
18−72 h, (IrCl2(Cp*))2 (0.1 mol %), sodium formate (5.00 mmol), water (5 mL), 40 °C, 15 h, isolated yield. 500 μmol scale. 100 μmol scale.
d
e
f
Yield in brackets corresponds to isolated aldehyde intermediate. 5.0 mol % 11 was used. 10 mol % 11 was used.
and reactivity for the aldol addition and reduction. (Details of
this prerequisite optimization are provided in the SI.)
suitable ligand for the transfer hydrogenation. With a 3-
aminophenol derived catalyst (R)-8, the effect of the different
amide residues on the rate of the aldol addition step was
noticeable, requiring 20 mol % catalyst loading and prolonged
reaction times. Structural simplification revealed that (R)-9 is
also suitable for CRSC, even with a reduced (RuCl2(p-
cymene))2 loading of 1.0 mol % (entry 7). Interestingly, (S)-
10 led to complete aldehyde reduction and lactonization within
2 h at 25 °C and confirmed that an (S)-configured catalyst
provides (S)-pantolactone. Intriguingly, the ethanolamine-
derived prolinamide (R)-11,14b which is readily available on a
large scale, provided (R)-pantolactone 1a with a reduced
catalyst/ligand loading of 5.0 and 1.0 mol %
(RuCl2(p‑cymene))2 within 4 h for the transfer hydrogenation
step.
Intriguingly, the initial results allowed us to identify a hybrid
between Noyori’s TsDPEN ligand and D-proline (R)-3 as a
suitable catalyst and ligand (Table 1)14,15 and t-BuOH as a
compatible solvent. More specifically, upon the completion of
the enantioselective aldol addition after 24 h, water,
(RuCl2(p‑cymene))2, and sodium formate (NaO2CH) were
added,16,17 providing (R)-pantolactone after 18 h with a 99%
conversion for both steps and an e.r. of 82:18. We next
confirmed the requirement of the amide moiety by using
pyrrolidinyl tetrazole (R)-4, which provided the expected
unreduced aldol addition product. We further examined
ethylene diamine or ethanolamine derivatives (R)-5−7 and
observed that also the hydroxy-terminated (R)-6 acts as a
C
DOI: 10.1021/acs.orglett.9b04033
Org. Lett. XXXX, XXX, XXX−XXX

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Organic Letters
Letter
Scheme 2. Mechanistic Proposal
To further refine the CRSC, we next studied the effect of
different transition-metal precursors, their loading, and the
optimal temperature for the transfer hydrogenation step
(Table 2). With a (RuCl2(p-cymene))2 precursor loading of
0.50 mol %, the aldehyde reduction required 26 h to reach near-
completion, whereas increasing the temperature to 40 °C
allowed us to reduce the reaction time to 6 h. The reaction time
could be further decreased to 1 h at 60 °C, and a slight increase
in reactivity was observed with (RuCl2(benzene))2, with almost
full conversion after 5 h at 40 °C. An even more significant
change in reactivity was observed when the transition metal was
changed to rhodium, with almost full conversion after only 2.5 h
at 40 °C, and iridium, with complete conversion in <1 h. Even
when the precursor loading was decreased to only 0.1 mol %, full
conversion could be achieved within 5 h at 40 °C. Satisfyingly,
the catalyst-repurposing sequential catalytic reaction under
these conditions was also readily applicable on a gram scale
(20 mmol), providing (R)-pantolactone (1a) in an overall 78%
yield and with an enantiomeric ratio of 86:14. Recrystallization
yielded enriched (R)-1a in an overall yield of 55% and with an
enantiomeric ratio of 98:2. (See the SI for details.) With the
optimal catalyst/ligand (R)-11 and reaction conditions for the
CRSC established, we evaluated the scope for a variety of
α‑disubstituted aldehydes (Table 3). For the synthesis of
(R)‑pantolactone 1a, the optimized conditions led to a
stereoselective aldol addition, transfer hydrogenation, lactoniza-
tion sequence with an overall yield of 62%, and 86:14
enantiomeric enrichment on a 1.00 mmol scale. Other alkyl
chains for products 1b and 1c gave enantioselectivities of 81:19
and 70:30 e.r., respectively. Notably, a change to cycloalkyl
substituents significantly increased the product selectivity to
enantiomeric ratios of up to 93:7 for the cyclobutyl product 1d.
Corresponding five- and six-membered derivatives 1e (e.r.
92:8) and 1f were also effectively prepared from commercially
available starting materials by CRSC. However, further
increasing the ring size (1g) or the introduction of an aromatic
substituent (1h) impacted the yield or the selectivity. Although
no significant diastereoselectivity was observed when applying
these reaction conditions to unsymmetric substrates, high
enantioselectivities were observed for the anti-configuration of
α-hydroxy lactones 1i−l.
The proposed mechanism of the sequential catalytic trans-
formation involves a first enamine formation from catalyst
(R)‑11 and isobutanal (Scheme 2), as observed by NMR when
equimolar amounts of the catalyst in t-BuOD-d10 were added
under similar conditions to the α-disubstituted aldehyde
substrate. (See the SI for details.) Monitoring the enantiose-
lectivity over the course of the subsequent aldol addition
reaction revealed only marginal variation, indicating the absence
of a competitive uncatalyzed background reaction. Furthermore,
a nonlinear effect was not noticeable when catalyst 11 with
different enantiomeric purities was employed. The catalytic
cycle A is then closed by hydrolysis, the secondary amine catalyst
is regenerated, and the aldol addition intermediate is in place for
the transfer hydrogenation cycle B. The addition of (IrCl2Cp*)2
allows to repurpose the regenerated prolinamide (R)-11 as a
ligand and, upon the addition of sodium formate, reduces
intermediate 2 to induce a direct lactonization, giving the
enantioenriched α-hydroxy-γ-butyrolactones. Having observed
the remarkable activity of this transfer hydrogenation system,
the Ir complex 12 was prepared by a stoichiometric addition of
ligand (R)-11 and Et3N to (IrCl2Cp*)2, which allowed us to
confirm its structure by X-ray crystallography. (See the SI for
details.)18
In conclusion, a CRSC strategy was developed and employed
in the preparation of enantioenriched α-hydroxy-γ-butyrolac-
tones by an economic and operationally simple protocol. The
prolinamide organocatalyst was thereby first used in a
stereoselective cross-aldol addition and subsequently repur-
posed as a ligand for a transition-metal-catalyzed transfer
hydrogenation. The later addition of the transition-metal
precursor upon aldol addition thus allowed to utilize otherwise
incompatible aldehyde substrates, which highlights the assets of
sequential catalysis in comparison with relay, tandem, or cascade
catalysis. Key industrial intermediates such as the vitamin B5
precursor (R)-pantolactone were readily available in an
D
DOI: 10.1021/acs.orglett.9b04033
Org. Lett. XXXX, XXX, XXX−XXX