Highly enantioselective synthesis of α-azido-β-hydroxy methyl ketones catalyzed by a cooperative proline-guanidinium salt system

Article abstract of DOI:10.1039/c3cc49371g

The combined activity of (S)-proline and an achiral tetraphenylborate TBD-derived guanidinium salt permits the aldol reaction between azidoacetone and aromatic, or heteroaromatic aldehydes. The α-azido-β-hydroxy methyl ketones obtained as products can be isolated in good yield, with high diastereo- and enantioselectivity. The Royal Society of Chemistry 2014.

Full text of DOI:10.1039/c3cc49371g

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Highly enantioselective synthesis of a-azido-
b-hydroxy methyl ketones catalyzed by a
cooperative proline–guanidinium salt system†
Cite this: Chem. Commun., 2014,
50, 2598
Received 10th December 2013,
Accepted 13th January 2014
´
Angel Martınez-Castaneda, Kinga Ke˛dziora, Ivan Lavandera,
´
˜
´
Humberto Rodrıguez-Solla, Carmen Concellon* and Vicente del Amo*
´
´
DOI: 10.1039/c3cc49371g
www.rsc.org/chemcomm
The combined activity of (S)-proline and an achiral tetraphenylborate
Proline is the most popular organocatalyst. This naturally
TBD-derived guanidinium salt permits the aldol reaction between occurring amino acid is cheap, readily available in both enantio-
azidoacetone and aromatic, or heteroaromatic aldehydes. The meric forms, and can be used for a wide range of synthetic
a-azido-b-hydroxy methyl ketones obtained as products can be transformations.6 With the aim of avoiding the use of other synthe-
isolated in good yield, with high diastereo- and enantioselectivity.
tically elaborated organocatalysts, our group4 and others7 have
demonstrated how the addition of additives can enhance the
Organic azides represent an important class of compounds, being reactivity and selectivity of this off-the-bench catalyst in classical
used as masks of amino functions, source of nitrenes, valuable transformations such as the aldol reaction. Moreover, the addition of
dipoles in [3+2]-dipolar cycloaddition reactions, and substrates in the additives can also expand the boundaries of proline as a catalyst. In
synthesis of iminophosphoranes for the aza-Wittig reaction.1 In this sense, we have reported the first proline-catalyzed asymmetric
this family, the densely functionalized a-azido-b-hydroxy ketones 1 synthesis of chlorohydrins through the intermolecular aldol reaction
possess a considerable synthetic value, showing up a particularly between chloroacetone and aromatic aldehydes, made feasible by
interesting chemical behaviour in comparison with simple alkyl or the participation of a guanidinium salt as an additive.4c
aryl azides.2 Compounds 1 are typically accessed by a base-promoted
aldol reaction of an a-azidoketone 2 and a non-enolizable aldehyde behaviour of our catalytic guanidinium salt–proline system towards
33 (Scheme 1).
a reaction like that illustrated in Scheme 1. 4-Nitrobenzaldehyde, 4a,
Motivated by our previous results, we decided to explore the
Although these protocols render the aldol adducts 1 with was adopted as the model substrate for preliminary reactions.
optimum chemical yield, undesired mixtures of anti and syn Azidoacetone (5, 1-azidopropan-2-one) was prepared on a multi-
isomers are always present. In fact, to our knowledge, there are gram scale, in 96% yield, from chloroacetone and sodium azide. In
no methodologies described in the literature that allow gaining correspondence with our previous work, we decided to evade the
access to a-azido-b-hydroxy ketones 1 in a controlled diastereo- use of any organic solvent, apart from ketone 5, which acts as both
and enantioselective manner. Following on with our studies on reagent and reaction medium.8 A careful optimization of the
organocatalysis,4 herein we report the first organocatalyzed stoichiometries involved in the reaction, time, temperature, as well
synthesis of enantioenriched anti-a-azido-b-hydroxy ketones 1,5 as the judicious choice of the anion accompanying the guanidinium
employing the cooperative participation of (S)-proline and a TBD salt, revealed ideal conditions (see ESI† for details, Tables S1–S5).
(triazabicyclo[4.4.0]dec-5-ene)-derived guanidinium salt.
So when a suspension of (S)-proline (10 mol%), guanidinium salt 6
(15 mol%) and 4-nitrobenzaldehyde 4a, in a moderate excess of
azidoacetone 5 (10 eq. respect to the aldehyde), was stirred for
120 hours at À10 1C, the a-azido-b-hydroxy ketone 7a was produced
in quantitative conversion, with good diastereo- (anti-7a/syn-7a, d.r.
90 : 10) and enantioselectivity (97% ee for anti-7a, Table 1, entry 1).
Although neither a-azido-b-hydroxy methyl ketone 7 has been
previously prepared, the relative spatial configuration of product 7a
could be unambiguously assigned considering the value of its 3JH–H
coupling constants, measured for the protons borne on carbons C4
(CH-OH) and C3 (CH-N3), on the 1H NMR spectra of the crude
reaction mixture (3Janti = 6.9 Hz; 3Jsyn = 3.3 Hz). These figures are in
Scheme 1
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´
Departamento de Quımica Organica e Inorganica, Universidad de Oviedo, C/Julian
´
Claverıa 8, 33006, Oviedo, Spain. E-mail: ccf@uniovi.es, vdelamo@uniovi.es
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
3
c3cc49371g
agreement with other JH–H coupling constants measured on
2598 | Chem. Commun., 2014, 50, 2598--2600
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Table 1 (S)-Proline/guanidinium salt 6 co-catalyzed synthesis of a-azido-
b-hydroxy ketones 7a–ia
to be appropriate substrates for this reaction, the corresponding
products 7h and 7i displaying good selectivity figures (Table 1,
entries 8 and 9). The tolerance of the reaction for heteroaromatic
aldehydes, challenging substrates in aldol-type C–C bond forming
reactions, confirms the reproducibility and robustness of this trans-
formation. Moreover, adducts anti-7a–i could be easily isolated by
flash chromatography on silica gel, affording analytically pure
products in high yield and with high ee. Also, it is important to
remark that the presence of the corresponding regioisomers 8a–i was
not observed in either of these transformations. A blank experiment
performed without additive 6 (Table 1, entry 10) presented a
significantly low conversion, as well as a poorer diastereomeric ratio
for the reaction product.11 It demonstrates the positive effect of the
guanidinium salt on the reaction course, which facilitates a reaction
that is not favorable with the single use of proline. Alternatively, the
sole presence of guanidinium salt 6 was insufficient for catalysing to
any extent the aldol reaction between aldehydes 4 and azidoacetone
5. Although the role played by the additive is not fully disclosed yet,
we postulate that the guanidinium core of salt 6 could form doubly
H-bonded motifs with the carboxylate function of proline, as well as
with the carbonyl moieties of ketone 5 and aldehydes 4, thus
enhancing their electrophilicity (reactivity).4a,b
Entry
ArCHO
Conversionb (%)
d.r.c
eed (%)
1
2
3
4
5
6
7
8
4a 4-NO2-C6H4
4b 3-NO2-C6H4
4c 2-NO2-C6H4
4d C6H5
4e 4-Cl-C6H4
4f 4-Br-C6H4
4g 4-CO2Me-C6H4
4h 2-furyl
>99 (90)
>99 (91)
99 (88)
>99 (84)
98 (85)
98 (84)
99 (83)
>99 (78)
>99 (80)
12
90 : 10
90 : 10
90 : 10
90 : 10
90 : 10
89 : 11
88 : 12
85 : 15
87 : 13
82 : 18
94
95
97e
95
94
95
95
93
88
n.d.
9
4i 2-pyridyl
4a 4-NO2-C6H4
10f
a
Reaction conditions: azidoacetone 5 (2.0 mmol), ArCHO (0.2 mmol),
(S)-proline (10 mol%), 6 (15 mol%), no solvent. The reaction mixture
was stirred for 120 h at À10 1C. Determined by 1H NMR spectroscopy
b
of the crude reaction mixtures. Conversion of aldehydes 4 (limiting
reagent) into a-azido-b-hydroxy ketones 7. The chemical yield of iso-
c
lated compounds anti-7 is given in brackets. Diastereoisomeric ratio
of anti- to syn-7 determined by 1H NMR spectroscopy of the crude
In order to determine the absolute stereochemical configuration
of the a-azido-b-hydroxy ketones 7, we contemplated the possibility
of crystallizing either of the compounds anti-7a–i for X-ray
diffraction experiments. Unfortunately, ketones 7a–i were all
isolated as oils or amorphous waxy solids. Also, attempts by us
to derivatize compounds anti-7 into other structures, whose
spatial configuration would be well determined in the literature,
resulted to be problematic.
d
reaction mixtures. Enantiomeric excess of analytically pure a-azido-b-
hydroxy ketones anti-7 as determined by HPLC analysis in chiral
e
stationary phases. Ketone 7c was isolated as an inseparable mixture
f
of anti- and syn-isomers. Reaction carried out without the addition of
guanidinium salt 6. The enantiomeric excess of the product was not
determined as a consequence of the low conversion.
As a plausible alternative, we considered the bioreduction of
the ketone moiety of diastereopure a-azido-b-hydroxy methyl
ketone anti-7d, used as a representative model, employing
stereocomplementary alcohol dehydrogenases (ADHs) with
2-propanol as the hydrogen source.12 In this sense, two ADHs, one
from Rhodococcus ruber (ADH-A)13 and another from Lactobacillus
brevis (LBADH)14 have shown excellent stereoselectivities towards the
reduction of, e.g. a-azido ketones15 and a-alkyl-b-keto esters,16 and
more importantly, with opposite stereopreference. Thus, ADH-A
affords selectively the corresponding (S)-alcohols while LBADH the
(R)-configured antipodes.17 This methodology opened up the possi-
bility of carrying out an orthogonal reduction of ketone anti-7d
giving access to the corresponding azido diols 11d and 12d in a
diastereomerically enriched form (Scheme 2). Densely function-
alized, chiral compounds such as 11d and 12d are not easily
3
Fig. 1 Reported JH–H values for different a-substituted-b-hydroxy
3
methyl ketones 9 and 10. Measured JH–H constants for compound 7a
are presented for comparison.
analogous anti- and syn-a-chloro-b-hydroxy methyl ketones 9,4c,9 and accessible by other synthetic methodologies available.
anti- and syn-a-methoxy-b-hydroxy methyl ketones 10,10 which are
Remarkably, both diols, 11d and 12d, were achieved with the
same diastereopurity (97%) coming from substrate anti-7d, demon-
well characterized in the literature (Fig. 1).
Subsequently, a set of aldehydes 4b–g, decorated with different strating that during the bioreduction process the ADH showed
functional groups and substitution patterns, were reacted with perfect stereoselectivity. Since the absolute configuration of the new
azidoacetone 5 under our finest reaction conditions (Table 1, alcohol function formed was known, measuring the coupling
entries 2–7). All of these reactions proceeded smoothly, with good constants between the protons at positions C2 (CH-N3) and C3
conversion and high anti-diastereoselectivity and enantioselectivity (CH3CH-OH) in diols 11d (3Jsyn = 2.6 Hz) and 12d (3Janti = 6.5 Hz),
(around 97% ee in all cases), independently of the nature of allowed the unambiguous assignation of the absolute stereo-
the aldehyde employed. Also, heteroaromatic aldehydes such as chemical configuration of the a-azido-b-hydroxy methyl ketones
2-furylcarboxaldehyde, 4h, and 2-pyridylcarboxaldehyde, 4i, proved anti-(3S,4S)-7 rendered from our organocatalyzed reaction.
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2600 | Chem. Commun., 2014, 50, 2598--2600
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