Organocatalytic asymmetric β-hydroxylation of α,β- unsaturated ketones

Article abstract of DOI:10.1002/ejoc.200700873

The highly enantioselective organocatalytic β-hydroxylation of α,β-unsaturated ketones was accomplished by using oximes as the oxygen-centered nucleophile. Optically active products are obtained with enantioselectivity up to 94 %. Central to these studies was the use of catalytic primary amine salt A, in which both the cation and the anion are chiral. Amine A exhibits high reactivity and selectivity for iminium-ion catalysis with enones. The potential interest of this novel transformation was demonstrated with the easy conversion of the Michael adducts in enantioenriched anti and syn 1,2-diols without erosion of the optical purity. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700873

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200700873
Organocatalytic Asymmetric β-Hydroxylation of α,β-Unsaturated Ketones
Armando Carlone,[a] Giuseppe Bartoli,[a] Marcella Bosco,[a] Fabio Pesciaioli,[a]
Paolo Ricci,[a] Letizia Sambri,[a] and Paolo Melchiorre*[a]
Keywords: Asymmetric catalysis / Conjugate addition / Ketones / Organocatalysis / Oximes
The highly enantioselective organocatalytic β-hydroxylation
of α,β-unsaturated ketones was accomplished by using ox-
imes as the oxygen-centered nucleophile. Optically active
products are obtained with enantioselectivity up to 94%.
Central to these studies was the use of catalytic primary
amine salt A, in which both the cation and the anion are chi-
ral. Amine A exhibits high reactivity and selectivity for imin-
ium-ion catalysis with enones. The potential interest of this
novel transformation was demonstrated with the easy con-
version of the Michael adducts in enantioenriched anti and
syn 1,2-diols without erosion of the optical purity.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
α,β-unsaturated ketones.[9] In particular, we have shown
that salt A, made by combining the easily available 9-
amino(9-deoxy)epi-hydroquinine[10] with -N-Boc phenyl-
glycine as the chiral counteranion, can function as a highly
efficient catalyst for the asymmetric conjugate addition of
indoles to simple enones;[9] the efficient activation relies on
the proven ability of primary amines to form iminium-ion
intermediates from ketones combined synergistically with
the benefits of asymmetric counterion directed catalysis.
Introduction
In recent years asymmetric organocatalysis has become
a field of central importance for the stereoselective prepara-
tion of chiral interesting compounds.[1] Novel modes of
substrate activation have been achieved that can deliver
unique, orthogonal, or complementary selectivities in com-
parison to metal-catalyzed processes. In particular, chiral
secondary amine catalysis has proven to be a powerful pro-
cedure for the enantioselective transformations of carbonyl
compounds. By exploiting distinct catalytic activation
modes such as enamine,[2] SOMO,[3] iminium-ion,[4] and di-
enamine[5] activation, aminocatalysis has enabled the asym-
metric α-, β-, and γ-functionalization of aldehydes with a
wide range of electrophiles and nucleophiles.[6] In compari-
son, little progress has been achieved in the corresponding
asymmetric functionalization of ketones, probably due to
the inherent difficulties of generating congested covalent in-
termediates from ketones and chiral secondary amines.
Recently, some reports have demonstrated the ability of
chiral primary amine derivatives to efficiently activate
ketones, owing to reduced steric constraints.[7] Meanwhile,
List and coworkers have introduced asymmetric counterion
directed catalysis (ACDC)[8] as an efficient strategy for
enantioselective transformations that proceed via cationic
Herein, we report the first highly chemo- and enantiose-
lective oxygen-centered addition of oximes to α,β-unsatu-
rated ketones catalyzed by chiral salt A, demonstrating the
generality and efficiency of this catalytic system as an imin-
ium-ion activator of simple enones
species, including iminium-ion intermediates. In this vein, Results and Discussion
we have developed a new catalyst primary amine salt, in
which both the cation and the anion are chiral, that exhibits
high reactivity and selectivity for iminium-ion catalysis with
β-Hydroxy ketones and the corresponding alkoxy ana-
logues constitute highly valuable chiral building blocks in
organic synthesis and structural recurring motifs in a vari-
ety of natural products. They are generally synthesized
either by aldol chemistry or the sequential epoxidation and
reduction of enones.[11] In contrast, the direct asymmetric
conjugate addition of O-centered nucleophiles to α,β-unsat-
urated ketones has proven a challenging task[12] mainly as
a consequence of the relative weakness of such nucleophiles
[a] Department of Organic Chemistry “A. Mangini”, Alma Mater
Studiorum – Università di Bologna
Viale Risorgimento 4, 40136 Bologna, Italy
Fax: +39-051-2093654
E-mail: pm@ms.fci.unibo.it
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
5492
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5492–5495

Asymmetric β-Hydroxylation of α,β-Unsaturated Ketones
coupled with problems associated with reaction reversibil- opposite enantiomeric counteranion (-N-Boc phenylgly-
ity.
cine) afforded the same enantiomeric product 3 with lower
Recently, oximes have been identified as suitable nucleo- reactivity and selectivity (Table 1, Entry 7), illustrating a
philes for a range of highly enantioselective catalytic oxa- marked case of a matched/mismatched catalyst–ion pair
Michael addition to electron deficient olefins.[13] Moreover, combination. On the basis of these studies, catalytic salt A
the oxime ethers resulting from this type of conjugate ad- was chosen as the best system and used for further optimi-
dition contain a labile N–O bond, which enables reductive zations.
cleavage to afford formal hydration products.
Interestingly, prolongation of the reaction time did not
With this in mind, a series of commercially available ox- improve the conversion, probably as a consequence of the
imes, 1, was screened in the addition to trans-3-nonen-2- reversibility of the process. Moreover, the products formed
one (2a) in the presence of catalytic salt A (1:2 ratio of in toluene slowly racemized after reaching the thermo-
amine to acid); the results of this survey are reported in dynamic equilibrium (Table 1, Entry 8). In order to circum-
Table 1. Despite the fact that (E)-benzaldehyde oxime (1a) vent this problem, an extensive study of the standard reac-
afforded the desired product with high enantioselectivity, tion parameters was performed, indicating solvent choice,
the reaction of commercially available 2,4-dimethoxybe- catalyst loading, and catalytic salt composition as the cru-
nzaldoxime (1d) with 2a in toluene was complete within 3 h cial factors. Evaluation of the reaction media (Table 1, En-
to yield the β-addition product with superior chemical and tries 9–12) led to the observation that carrying out the reac-
optical yield (89% ee; Table 1, Entry 4).
tion in Et2O provided comparable results in terms of both
yield and enantioselectivity with respect to toluene (Table 1,
compare Entries 4 and 12) but, more importantly, without
erosion of the enantiomeric purity during time (Table 1, En-
try 13). This condition allowed the catalyst loading to be
reduced to 10 mol-% (1:2 ratio of amine to acid) without
affecting the efficiency of the system (Table 1, Entry 14). In
addition, variation of the reaction temperature with the aim
to improve the yield and enantiopurity did not provide use-
ful results (Table 1, Entries 15, 16).
Table 1. Screening results for the organocatalytic addition of aro-
matic oximes to enone 2a.[a]
Importantly, a survey of the catalytic salt composition
revealed that whereas a 1:1 ratio of 9-amino(9-deoxy)epi-
hydroquinine to -N-Boc phenylglycine had a detrimental
impact on reactivity, a 1:1.5 ratio represented the best com-
promise between catalyst loading and catalytic efficiency
(Table 1, Entries 17, 18).
Entry Oxime
Solvent
Catalytic salt A
Yield
[%][b]
ee
% amine % acid
[%][c]
1
2
3
1a
1b
1c
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
AcOEt
hexane
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
20
20
20
20
20
20
20
20
20
20
20
20
20
10
20
10
10
10
40
40
40
40
40
40
40
40
40
40
40
40
40
20
40
20
10
15
22
75
31
55
50
49
48
56
52
46
42
52
53
55
49
49
31
52
86
32
66
89
50
80
82
81
76
86
72
90
90
90
91
80
90
90
After optimization of the catalytic system, the scope of
this novel organocatalytic β-hydroxylation was explored by
using the conditions reported in Table 2. Different linear
α,β-unsaturated ketones underwent the reaction smoothly
to afford optically active oxime addition products 3 in mod-
erate-to-good yields and high enantioselectivities (up to
94% ee). Notably, the mild reaction conditions adopted are
tolerant of the silyl ether functionality (Table 2, Entry 7).
Variation in the steric contribution of the R2 ketone sub-
stituents revealed that the more encumbered ethyl group en-
genders higher stereoselectivity, albeit with slightly lower re-
activity (Table 2, Entries 1, 2 and 3, 4). Practical limitations
of the method include prohibitively slow reaction rates with
enones bearing aromatic or highly hindered β substituents.
A demonstration of the synthetic utility of this novel or-
ganocatalytic reaction is presented in the stereoselective
preparation of optically active syn- or anti-configured 1,3-
diols (Scheme 1), highly valuable chiral structural motifs
present in many polyketide-derived natural products of
proven biological activity.[15] The asymmetric oxime ad-
dition to 2e under our catalytic conditions, followed by sim-
4
5[d]
6[e]
7[f]
8[g]
9
10
11
12
13[g]
14[h]
15[i]
16[j]
17[k]
18[k]
[a] Reactions were carried out at room temperature by using
3 equiv. of oxime on a 0.1 mmol scale. [b] Yield of isolated product.
[c] The ee value of 3 was determined by HPLC analysis. [d] TFA
was used as counteranion. [e] -N-Boc phenylalanine was used as
chiral counteranion. [f] -N-Boc phenylglycine was used as chiral
counteranion. [g] Reaction time: 24 h. [h] Reaction time: 18 h. [i]
Reaction carried out at 0 °C for 18 h. [j] Reaction carried out at
reflux for 18 h. [k] Reaction time: 40 h.
The results obtained with different counteranions (e.g., ple reductive cleavage, provided formal hydration product 4
trifluoroacetic acid, -N-Boc phenylalanine; Table 1, En- with minimal erosion of the optical purity (88% ee). This
tries 5, 6) did not bring any appreciable improvement.[14] process enabled the verification of the absolute configura-
Remarkably, as previously observed,[9] employment of the tion of the β-hydroxy ketone 4 by comparison of the mea-
Eur. J. Org. Chem. 2007, 5492–5495
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5493

P. Melchiorre
SHORT COMMUNICATION
tilled Et2O without any precautions to exclude water. In an ordi-
nary test tube equipped with a magnetic stirring bar, 9-amino(9-
deoxy)epi-hydroquinine (10 or 20 mol-%) and -N-Boc phenylgly-
cine (15 or 30 mol-%) as the chiral counteranion were dissolved in
Et2O (1 mL). The solution was stirred for 20 min at room tempera-
ture to allow the formation of catalytic salt A. After the addition
of α,β-unsaturated ketones (0.2 mmol), the mixture was stirred at
room temperature for 10 min. Then, oxime (0.6 mmol, 3 equiv.) was
added in one portion. The tube was then closed with a rubber stop-
per and stirring was continued for the indicated time. The crude
reaction mixture was diluted with hexane (2 mL) and flushed
through a plug of silica (hexane/Et2O, 1:1). The solvent was re-
moved in vacuo, and the residue was purified by flash chromatog-
raphy to yield the desired product.
Table 2. Scope of the organocatalytic asymmetric β-hydroxylation
of α,β-unsaturated ketones with the use of oxime 1d.[a]
Entry
R1
R2
Catalytic salt A
% amine % acid
t
[h]
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
pentyl
pentyl
Me
Me, 2a
Et, 2b
Me, 2c
Et, 2d
10
20
10
20
10
20
20
15
30
15
30
15
30
30
40
48
40
60
40
55
60
(3a)52
(3b)56
(3c) 53
(3d)46
(3e) 55
(3f) 55
(3g)35
90
94
80
88
90
92
80
Me
PhCH2CH2 Me, 2e
propyl Et, 2f
CH2OTIPS Et, 2g
2,4-Dimethoxybenzaldehyde O-[1-(2-Oxopropyl)hexyl]oxime (3a):
The reaction was carried out at room temperature for 40 h follow-
ing the general procedure (Table 2, Entry 1). The title compound
was isolated by column chromatography (hexane/acetone, 95:5) in
52% yield and 90% ee. The ee was determined by HPLC analysis
by using a Chiralcel OD-H column (hexane/iPrOH, 80:20; flow rate
0.75 mLmin–1; λ = 214, 254 nm; τminor = 6.2 min; τmajor = 6.5 min).
[α]rD.t. = +2.8 (c = 1.2, CHCl3, 90% ee). 1H NMR (400 MHz,
CDCl3): δ = 0.88 (t, J = 6.8 Hz, 3 H), 1.21–1.50 (m, 6 H), 1.52–
1.75 (m, 2 H), 2.20 (s, 3 H), 2.56 (dd, J = 7.4, 15.6 Hz, 1 H), 2.86
(dd, J = 4.8, 15.6 Hz, 1 H), 3.80 (s, 3 H), 3.81 (s, 3 H), 4.55–4.61
(m, 1 H), 6.41 (d, J = 2.4 Hz, 1 H), 6.48 (dd, J = 2.4, 8.8 Hz, 1 H),
7.67 (d, J = 8.8 Hz, 1 H), 8.34 (s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 13.4, 22.5, 25.0, 30.9, 31.7, 34.0, 48.6, 55.4, 55.5, 79.4,
98.1, 105.4, 113.9, 127.2, 144.2, 158.7, 162.3, 207.7 ppm. HRMS:
calcd. for C18H27NO4 321.1940; found 321.1943.
6
7[d]
[a] Reactions were carried out at room temperature by using
3 equiv. of 1d on a 0.2 mmol scale. [b] Yield of isolated product. [c]
The ee value of 3 was determined by HPLC analysis. [d] TIPS:
triisopropylsilyl.
sured optical rotation with the value reported in the litera-
ture.[16,17] The stereoselective syn or anti reduction[18] of 4
furnished corresponding 1,3-diols 5 with preserved optical
purity (88% ee) and the desired relative stereochemistry.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and full characterization.
Acknowledgments
This research was carried out within the framework of the National
Project “Stereoselezione in Sintesi Organica” supported by MIUR,
Rome, and FIRB National Project “Progettazione, preparazione e
valutazione farmacologica di nuove molecole organiche quali pot-
enziali farmaci innovativi”.
Scheme 1. Stereoselective route to optically active syn- or anti-con-
figured 1,3-diols.
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Conclusions
We have disclosed the first catalytic and highly enantiose-
lective β-hydroxylation of α,β-unsaturated ketones by using
aromatic oximes as the O-centered nucleophiles and cata-
lyzed by primary amine salt A, in which both the cation
and the anion are chiral. Besides establishing the generality
and the efficiency of this new catalytic system as an imin-
ium-ion activator of simple enones, this novel organocata-
lytic transformation shows potential applicability to the
synthesis of polyketide-derived natural products.
[2] For recent reviews, see: a) B. List, Chem. Commun. 2006, 819–
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Experimental Section
General Procedure for the Organocatalytic β-Hydroxylation of α,β-
Unsaturated Ketones: All the reactions were carried out in undis-
[5] S. Bertelsen, M. Marigo, S. Brandes, P. Dinér, K. A. Jørgensen,
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5494
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5492–5495

Asymmetric β-Hydroxylation of α,β-Unsaturated Ketones
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[14] In the absence of an acidic counteranion, the 9-amino(9-deoxy)-
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proceeding through the activation of the oxime by hydrogen
bonding to the basic quinuclidine nitrogen atom. For this type
of activation of oximes in asymmetric organocatalytic Michael
additions, see ref.[13d]
[15] a) S. E. Bode, M. Wolberg, M. Müller, Synthesis 2006, 557–
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[17] The sense of the stereochemical induction, on the basis of the
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with the observation made in the previously reported Michael
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iminium-ion intermediate to understand the origin of the
enantioselectivity are ongoing and will be reported in due
course.
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Received: September 14, 2007
Published Online: October 9, 2007
Eur. J. Org. Chem. 2007, 5492–5495
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5495