Carbohydrates as efficient catalysts for the hydration of α-amino nitriles

Article abstract of DOI:10.1039/c6cc07530d

Directed hydration of α-amino nitriles was achieved under mild conditions using simple carbohydrates as catalysts exploiting temporary intramolecularity. A broadly applicable procedure using both formaldehyde and NaOH as catalysts efficiently hydrated a variety of primary and secondary susbtrates, and allowed the hydration of enantiopure substrates to proceed without racemization. This work also provides a rare comparison of the catalytic activity of carbohydrates, and shows that the simple aldehydes at the basis of chemical evolution are efficient organocatalysts mimicking the function of hydratase enzymes. Optimal catalytic efficiency was observed with destabilized aldehydes, and with difficult substrates only simple carbohydrates such as formaldehyde and glycolaldehyde proved reliable.

Full text of DOI:10.1039/c6cc07530d

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Carbohydrates as Efficient Catalysts for the Hydration of α-Amino
Nitriles
Received 00th January 20xx,
Accepted 00th January 20xx
Sampada Chitale, Joshua S. Derasp, Bashir Hussain, Kashif Tanveer, André M. Beauchemin*
Directed hydration of α-amino nitriles was achieved under mild conditions using simple carbohydrates as catalysts
exploiting temporary intramolecularity. A broadly applicable procedure using both formaldehyde and NaOH as catalysts
efficiently hydrated a variety of primary and secondary susbtrates, and allowed the hydration of enantiopure substrate to
proceed without racemization.This work also provides a rare comparison of the catalytic activity of carbohydrates, and
shows that the simple aldehydes at the basis of chemical evolution are efficient organocatalysts mimicking the function of
hydratase enzymes. Optimal catalytic efficiency was observed with destabilized aldehydes, and with difficult substrates
only simple carbohydrates such as formaldehyde and glycolaldehyde proved reliable.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Hydration and hydrolysis reactions are of fundamental findings from a prebiotic chemistry perspective.12 Surprisingly,
importance in chemistry and biochemistry. Indeed, many procedures using catalytic amounts of carbonyl compounds
enzymes have evolved to perform these reactions under were not reported, and the applicability of this procedure
remarkably mild conditions, notably allowing the hydrolysis of appeared mostly limited to primary
α-amino nitriles. In
lipids,1 glycosides,2 peptides,3 phosphates,4 and DNA.5 The addition, reactions of enantiopure substrates were not
development of synthetic catalysts which replicate the reported, and since then aldehyde-catalyzed racemization
efficiency of these enzymes has been a long standing challenge reactions have been reported for related substrates.13 Given
in organic synthesis. Specifically, the hydration of nitriles that reactions operating via temporary intramolecularity can
typically requires harsh conditions and in recent years, several be 104-108 times faster than intermolecular variants,14 we
metal catalysts have been developed to achieve hydration with speculated that a broadly applicable, yet milder truly catalytic
high selectivity under relatively mild conditions.6,7 However, protocol could be developed. From a prebiotic chemistry
the selective hydration of
industrially-relevant transformation that typically requires catalytic activity of simple carbohydrates, a simple question
harsh acidic conditions to form the desired -amino amides which to our knowledge has not been addressed. Herein, we
α-amino nitriles is a difficult, perspective, this also offered the opportunity to compare the
α
and acids (e.g. strong acids, heat, up to 48 h).8 From a prebiotic report such a study and the development of an efficient and
chemistry/chemical evolution perspective,9 the hydration and versatile system for the directed hydration of
α
-amino nitriles
hydrolysis of amino nitriles are of remarkable importance. The using formaldehyde as catalyst (Scheme 1b).
generally accepted path to
molecules (e.g. the Miller experiment9a) requires the hydration
and hydrolysis of -amino nitriles (Strecker adducts). In
α-amino acids from simpler
a) Commeyras et al.:
O
α
R
O
R
addition, hydration of other amino nitriles obtained from HCN
oligomerization is required for key prebiotic molecules, for
example the formation of guanine.9b,10 In contrast, decades
ago Commeyras, Taillades and Pascal pioneered the use of
carbonyl compounds as promoters operating via temporary
intramolecularity (Scheme 1a).11 They notably showed that
R
(1-5 equiv)
HN
C
NH2
H2N
N
H2N
CN
NaOH (0.2-10 equiv)
H2O, rt
Na
O
105 rate acceleration prevents substrate degradation
but stoichiometric in both ketone and base
b) This work:
R
R
R
HCHO
R'
NH2
10-20 mol%
20 mol%
R'
α-amino nitriles can be hydrolyzed readily using stoichiometric
quantities of aldehydes or ketones and excess NaOH, studied
HN
C
N
N
CN
H
N
H
O
NaOH
O Na
23 examples
this reaction in detail, and noted the importance of their
ee is preserved
only simple carbohydrates are broadly applicable catalysts!
Scheme 1 Carbonyl-promoted and carbonyl-catalyzed hydrations
We have recently used temporary intramolecularity in
aldehyde-catalyzed hydroaminations. In this context,
aldehydes can act as tethering catalysts, and the transient
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intramolecularity present in mixed aminal intermediates observed using formaldehyde as catalyst: 70% yield, and thus
enabled room temperature intermolecular hydroaminations of >3 turnovers within 15 minutes at room temperature (2i).
allylic amines.15 This work also established that chiral Overall, these results showed a clear catalyst structure-activity
aldehydes can be efficient asymmetric catalysts (up to 97% relationship, with destabilized aldehydes (2h-i, 2m) and
ee).15a-b
Table 1 Carbonyl catalyst scan with secondary α-amino nitrile 1b.a
O
catalyst (20 mol%)
NaOH (20 mol%)
O
catalyst (20 mol%)
NaOH (20 mol%)
MeS
CN
NH2
MeS
CN
NH
NH2
Ph
Ph
NH2
3b
H2O, rt
NH2
3a
1a
H2O, rt
NH
1b
O
O
O
O
A
HO
OH
F
F
HO
Ph
H
H
Catalyst
Time
24 h
Yield (%)b
2a
2 h, 2%
2d
3 h, 53%
2f
30 min, 61%
2h
No
catalyst
No catalyst
15
86
15 min, 65%
O
45 min
O
No catalysis observed
3-12 h
5-19%a
O
O
O
H
O
O
H
H
H
Me
H
H
H
O
O
2i
O
2b
2 h, 17%
O 2c
2 h, 32%
2e
2 h, 65%
2g
30 min, 66%
2i
O
1.5h
69
52
15 min, 70%
Ph
H
H
HO
catalytic activity
Low
carbohydrates
High
H
2h
O
B
O
O
O
2.5 h
OH
O
O
O
Me
D-ribose (2j)
12 h, 55%b
HO
OH
HO
H
HO
H
H
H
2d
2i
2l OH
OH
a
b
D-glucose (2k)
18 h, 54%b
15 min, 70% (w/ NaOH)
2m
2 h, 65%
3 h, 20%
4 h, 89%[b]
Conditions: see Scheme 2. NMR yield using 1,3,5-trimethoxybenzene as
2.5 h, 71% (w/ pH 11 buffer)
internal standard.
Scheme 2. Carbonyl catalyst scan with primary α-amino nitrile 1, including several
carbohydrates. Conditions: nitrile (1 equiv), catalyst (0.2 equiv), NaOH (0.2 equiv) in
ketones (e.g. 2f-g) displaying optimal reactivity. In contrast,
stable aldehydes (e.g. 2a) and C4-C6 carbohydrates able to
form stable cyclic hemiacetal derivatives (e.g. 2j-l) displayed
poor catalytic activity. Overall, this catalytic efficiency profile
suggests that the pre-equilibrium for the formation of the
hemiaminal intermediate is important, and we were interested
in probing the generality of this finding.
a
H2O (1M). NMR yields using an internal standard are shown. Significant degradation
was observed. b Using 1 equiv of carbohydrate.
Mechanistic work highlighted the importance of the catalyst
structure in accessing
a
favourable "preassociation"
equilibrium,15c and identified destabilized aldehydes as
particularly efficient catalysts (e.g. formaldehyde: 5 mol%).8c-d
This study suggested that a preassociation event could also be
present in carbonyl-promoted and carbonyl-catalyzed directed
More hindered, secondary
optimization substrates due to their relevance as precursors of
natural and unnatural -amino acids. Arguably, hemiaminal
α-amino nitriles were attractive
α
reactions.16,17
Moreover,
unfavourable
preassociation
formation could also be less kinetically and thermodynamically
favorable with such hindered substrates. Thus, many carbonyl
compounds were screened as potential catalysts for the
equilibria could account for the fact that most carbonyl
"catalyzed" reactions require a stoichiometric amount of the
carbonyl promoter.18 Thus we embarked on a reinvestigation
hydration of secondary α-amino nitrile 1b (Table 1).
of the hydration of α-amino nitriles, to achieve high catalytic
efficiency, establish a broadly applicable procedure, and probe
the importance of this preassociation equilibrium. First,
several carbonyl compounds were screened for their ability to
In contrast to the results shown in Scheme 2, few carbonyl
compounds catalyzed the hydration of -amino nitrile 1b
α
(Table 1). To our delight, formaldehyde showed excellent
catalytic activity, glycolaldehyde again showed good catalytic
activity, and dihydroxyacetone proved catalytically active.
However, no catalysis was observed with most aldehydes and
ketones, including with acetone and cyclic ketones typically
used by Commeyras et al. in related stoichiometric reactions.11
This reactivity trend suggests that the hemiaminal pre-
equilibrium (i.e. the preassociation step resulting in temporary
intramolecularity) is critical in the catalyzed hydration of
catalyze the hydration of primary α-amino nitrile 1a (Scheme
2A), which provided the opportunity to compare the catalytic
efficiency of several carbohydrates (Scheme 2B).
Gratifyingly, catalytic turnover was observed for the
hydration of primary α-amino nitrile 1a using several
aldehydes (2h-i, 2m) and ketones (2d-g). These results show
that the structure of the carbonyl catalyst is not critical for
primary α-amino nitriles. This is in agreement with results by
secondary α-amino nitriles. This trend also mirrors the catalyst
Commeyras et al., who showed that formation of the required
hemiaminal intermediate is facile and does not influence the
efficiency of the hydration reaction (under stoichiometric
conditions).11c However, some catalysts proved surprisingly
inefficient (2a-c), especially in contrast to the rapid reactions
structure-activity relationship observed in aldehyde-catalyzed
Cope-type hydroaminations.15 To further delineate the scope
of this catalytic hydration procedure, several primary and
secondary α-amino nitriles were subjected to conditions using
catalytic formaldehyde and NaOH (Table 2).
2 | J. Name., 2012, 00, 1-3
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stable cyanide ion, with minimal hydration product being
Gratifyingly, hydration of various primary and secondary observed. Importantly, the reaction of enantioenriched
α-amino nitriles proceeded at room temperature in the substrates occurred without erosion in enantiopurity (3v-w), a
presence of 20 mol% of both formaldehyde and NaOH (Table key requirement for potential uses in the synthesis of
2). This procedure proved efficient for most substrates:
unnatural α
-amino acids.8,20
Table 2 Formaldehyde-catalyzed hydration of α-amino nitriles under basic conditionsa
In summary, a fast, carbonyl-catalyzed reaction allows
room-temperature hydration of variety of structurally
diverse -amino nitriles. This work exploits the propensity of
O
a
O
R2
(20 mol%)
O
R2
R1
R2
R1
HN
CN
α
H
H
R1
OH
NH2
N
formaldehyde to preassociate, and the temporary
intramolecularity that results from an hemiaminal
intermediate to achieve truly catalytic directed hydrations
under mild reaction conditions. This new procedure for the
NaOH (20 mol%)
H2O, rt
HN
N
R3
R3
3c-w
R3
4
1c-w
hydration of
harsh acidic conditions typically required for the formation of
valuable -amino acid derivatives. In addition, this work
α-amino nitriles constitutes an alternative to the
α
establishes that several carbohydrates are efficient hydration
catalysts and allows a comparison of their efficiency, thus
addressing an important void in the literature. Efforts are
ongoing to extend the scope of this directed hydration
procedure to other substrates, improve catalytic activity, and
explore asymmetric variants.
Acknowledgements
Acknowledgment is made to the donors of The American
Chemical Society Petroleum Research Fund for support of this
work. Other support from NSERC (Discovery, Discovery
Accelerator Supplement and CREATE grants) and the
University of Ottawa is gratefully acknowledged. Menachem
Benzaquen is thanked for experimental assistance. We are also
thankful to the Simons Foundation for recent support of
related efforts. OGS (B.H. and J.S.D.) and NSERC (B.H.) are
thanked for graduate scholarships. A.M.B. also expresses his
gratitude to Profs Bode, Carreira, Chen, Eschenmoser, Hilvert
and Wennemers for stimulating discussions related to this
work during a sabbatical at the LOC, ETH Zürich.
a
Conditions: see Scheme 2, using formalin (37 wt% in H2O) as formaldehyde
b
source. Isolated yields are provided. 1:1 mixture of MeCN/H2O was used as
solvent. c 80 mol% HCHO was used in a 1:9 mixture of i-PrOH/H2O as solvent. d 10
e
mol% HCHO was used; NMR yield using an internal standard. 80% yield was
obtained with 10 mol% HCHO, 2 M in α-amino nitrile. f 40 mol% HCHO was used.
substitution was well tolerated at the C
alkyl 3d-l 3p-t and aryl 3m-n substituents. Various
N-substituents were also tolerated, including N-alkyl groups
3c 3g-j, 3n-r), and hydrazine 3s or N-acetyl 3t
α position, including
(
,
)
(
)
(
,
(
)
( )
Notes and references
functionalities. Several other functional groups including
benzyl ethers (3f), terminal alkynes and alkenes (3p-q) could
also be present in the substrates. A higher catalyst loading (40
mol%) was required for hindered carboxamide 3o since for this
substrate degradation was a competitive reaction. Conversely,
the reaction was also efficient at a lower catalyst loading (10
mol%) for the formation of product 3n. This is remarkable
considering that formation of imidazolidinone 4n was
observed under the reaction conditions, and such adduct could
be a source of catalyst inhibition.19 For all substrates, the
reaction proceeded rapidly despite the heterogeneous nature
of the reaction; however, the use of an organic co-solvent
proved necessary for the formation of product 3l. Reaction
time varied based on substrate structure, but all reactions
were remarkably faster, cleaner and more efficient compared
to the background reactions in the absence of formaldehyde
which typically caused substrate degradation to form the more
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