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Organocatalyzed Asymmetric -Aminoxylation of Aldehydes and KetonesЧAn Efficient Access to Enantiomerically Pure -Hydroxycarbonyl Compounds Diols and Even Amino Alcohols.

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Angewandte
Chemie
Asymmetric Catalysis
Organocatalyzed Asymmetric a-Aminoxylation of
Aldehydes and Ketones—An Efficient Access to
Enantiomerically Pure a-Hydroxycarbonyl Compounds,
Diols, and Even Amino Alcohols
Pedro Merino* and Tomas Tejero
Keywords:
aldehydes · asymmetric catalysis · ketones ·
oxidation · proline
The asymmetric installation of a hydroxy group at the position a to a
carbonyl function is an important C O
bond-forming process in organic synthesis.[1] The resulting optically active ahydroxy carbonyl compounds are of
general interest since they provide direct routes to a vast number of biologically significant compounds including carbohydrates, antibiotics, alkaloids,
and terpenes. The most widely used
direct procedure for preparing optically
active a-hydroxy carbonyl compounds is
the oxidation of enolates with an oxidizing reagent.[2] Asymmetry is induced by
using either chiral nonracemic enolates
with achiral reagents or prostereogenic
enolates and enantiomerically pure oxidizing reagents, typically N-sulfonyloxaziridines.[3] Alternative to these chemical methods a variety of a-oxy-functionalized carbonyl compounds, including a-hydroxy, a-hydroperoxy, and aacetoxy derivatives, can also be prepared in enantiomerically pure form by
biocatalytic methods.[4]
Despite the emergence during the
two last decades of new efficient and
convenient enantioselective catalytic
processes,[5] not many methods are
known for the catalyzed asymmetric
addition of electrophiles to enolates.[3, 6]
The asymmetric a-amination of aldehydes and ketones provides a useful
reference point for the reaction described in this account.[7]
Among the electrophiles that can be
used to introduce a heteroatom at the a
position of a carbonyl group, nitroso
compounds[8] are particularly attractive
because of the presence of two different
electrophilic centers (N and O atoms)
that could lead to either N- or Oalkylation, provided the regioselectivity
of the reaction can be controlled
(Scheme 1).
reaction illustrated in Scheme 1 resulted
from the Lewis acid catalyst; the best
results were obtained with Et3SiOTf.[10]
Under these conditions both silyl and tin
enolates provided the a-aminoxy carbonyl compounds 4. In order to introduce asymmetry in the reaction it was
conducted in the presence of (R)-binap
(binap = 2,2’-bis(diphenylphosphanyl)1,1’-binaphthyl) and 10 mol % AgOTf.
Complete O-selectivity with 91 % ee
was observed, and of the various silver
salts surveyed, the AgOTf and AgClO4
complexes gave the best results in terms
of both enantio- and regioselection
(Scheme 2).[11] The reaction was tested
with various tin enolates and, in all
cases, O-regioselectivity and enantioselectivity were maintained. The further
transformation of a-aminoxy ketone 6
into a-hydroxy ketone 7 was smoothly
Scheme 1. N- vs. O-alkylation of carbonyl
compounds in the reaction with nitrosobenzene.
[*] Dr. P. Merino, Dr. T. Tejero
Laboratorio de Sintesis Asimetrica
Departamento de Quimica Organica
Facultad de Ciencias
Universidad de Zaragoza
50009 Saragossa, Aragon (Spain)
Fax: (+ 34) 976-762-075
E-mail: pmerino@unizar.es
Yamamoto and co-workers approached this problem by using lithium
and tin enolates, in the absence of any
catalyst, to generate the corresponding
a-hydroxyamino carbonyl compounds
3.[9] The regiochemical control of the
Angew. Chem. Int. Ed. 2004, 43, 2995 –2997
DOI: 10.1002/anie.200301760
Scheme 2. Asymmetric, catalyzed nitroso-aldol
reaction of tin enolate 5 with nitrosobenzene.[11]
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2995
Highlights
carried out with a catalytic amount
(0.3 equiv) of CuSO4 in methanol. The
selectivity found for ketone 7 was
97 % ee.
During the past five years there has
been a dramatic upsurge of interest in
asymmetric non-transition-metal-catalyzed reactions,[12] particularly those
concerning aminocatalysis in which a
carbonyl group is activated by a chiral
amine.[13] In this context, (S)-proline,
which can serve as a ligand in asymmetric transition-metal-catalyzed reactions,
has been also found to be an excellent
catalyst by itself[14] for reactions of
carbonyl compounds,[15] including the
a-amination of aldehydes and ketones.[7]
Last year several reports appeared in
which a-aminoxylated aldehydes and
ketones 4 were prepared in enantiomerically pure form from the parent carbonyl compounds and nitrosobenzene
with (S)-proline as the catalyst
(Scheme 1). The advantages of this
organocatalyzed transformation are
clear: 1) the asymmetric reaction is
carried out by a metal-free catalyst,
and 2) no enolates must be preformed.
The groups of MacMillan[16] and Hayashi[17] and also Zhong[18] reported almost simultaneously the direct (S)-proline-catalyzed enantioselective a-aminoxylation of aldehydes (Scheme 3).
Scheme 3. Enantioselective (S)-proline-catalyzed a-aminoxylation of aldehydes. TIPS = triisopropylsilyl.[16]
In contrast to other proline-catalyzed asymmetric reactions,[15] which
require up to 47 mol % catalyst,[19] the
reaction outlined in Scheme 3 is efficiently catalyzed even with catalyst
loadings as low as 0.5 mol % as MacMillan et al. demonstrated.[16] The use of
2 mol % is, however, more advisable in
order to maintain expedient reaction
times.
Almost as interesting as the high
enantioselectivity observed for 9 is the
preferred O-regioselectivity. In princi-
2996
ple, trends similar to those observed for
tin enolates in the absence of any
catalyst (N-alkylation) might be expected for the reaction of the intermediate
enamine (a masked enolate), which is
formed upon activation of the aldehyde.
However, only O-alkylation is observed
in all cases. This means that additional
directing features are needed to ensure
attack at the oxygen atom. Proline
meets such a requirement due to the
presence of the carboxyl group which
may favor a transition state A with an
intramolecular hydrogen bond stabilized by the enhanced Brønsted basicity
of the nitrogen atom (Scheme 4). Model
A has been proposed essentially in the
same, but independent, way by the
groups of MacMillan,[16] Hayashi,[17]
and Zhong,[18] and it follows the previously reported mechanistic considerations for (S)-proline-catalyzed reactions
such as a C=C bond, Si-protected hydroxy groups, and N-Boc amino groups,
and variation in the steric demand of the
aldehyde did not affect the reaction in
terms of efficiency or enantioselectivity.
A considerable broadening of the
scope of the reaction has been recently
achieved with the extension to ketones.
Cordova and co-workers[20] as well as
Hayashi and co-workers[21] reported simultaneously
the
organocatalyzed
asymmetric a-aminoxylation of ketones
(Scheme 5). Condensation of an excess
Scheme 5. Asymmetric a-aminoxylation of
ketones.
(2.0 to 10.0 equiv) of
cyclohexanone
12
with 1.0 equiv nitrosobenzene in a highly
polarized solvent such
as DMSO or DMF
and in the presence
of a substoichiometric
amount (5–30 mol %)
of (S)-proline provided opportunities to
examine the behavior
of the reaction under
a variety of experimental
conditions.[20, 21] Although
excellent enantioselectivities were observed for compound
13, low chemical
yields and consideraScheme 4. Catalytic cycle for the (S)-proline-catalyzed a-aminoxyble amounts of the
lation of carbonyl compounds.
corresponding a,a’bis(aminoxylated)
of ketones and aldehydes with electro- product were also obtained. Synthetiphiles.[7, 13] It is important to emphasize cally useful chemical yields and comthat while model A is consistent with plete a-monoaminoxylation were possiexperimental data collected to date, it ble by slow addition (syringe pump) of
still needs a firmer foundation. Of nitrosobenzene to the reaction mixture.
course, our understanding of the details The extension to other cyclic ketones
of proline-catalyzed reactions will resulted in excellent yields as well as
almost complete regio- and enantiosechange with time and experience.
The reaction appears to be quite lectivities. Unfortunately, acyclic kegeneral since both aliphatic and aromat- tones gave unfavorable mixtures of Oic aldehydes gave good results. Even the and N-alkylated products; in all cases,
presence of several functional groups, with the exception of 3-butenyl methyl
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2004, 43, 2995 –2997
Angewandte
Chemie
ketone, the O-alkylated adduct was the
major product.
a-Aminoxylated carbonyls can be
transformed readily into the corresponding a-hydroxy carbonyls and then
reduced to diols without any loss in
optical purity.[11] The reduction of the
carbonyl moiety can also be made in situ
prior to cleavage of the the N O bond
(NaBH4)[20] or in a simultaneous way
(NaBH4, Pd/C, H2),[16] thus providing an
alternative, synthetically attractive solution, in the case of a-hydroxy aldehydes (Scheme 6, R1 = H), to the asym-
tility of the reaction are impressive
advantages that should facilitate the
synthesis of many useful small molecules possessing not only the a-hydroxycarbonyl unit but also other functionalities such as diols or amino alcohols.
Undoubtedly, all these possibilities
should provide synthetic tools for the
asymmetric synthesis of collections of
molecules with high levels of diversity
directed to the recently proposed “diversity-oriented synthesis”.[22]
[7]
[8]
[9]
Published Online: May 13, 2004
[10]
[11]
[12]
[13]
[14]
[15]
[16]
Scheme 6. Synthetic applications of the asymmetric organocatalyzed a-aminoxylation of aldehydes and ketones.
[17]
metric dihydroxylation of terminal olefins. Scheme 6 illustrates the potential of
the enantioselective a-aminoxylation of
aldehydes and ketones for the synthesis
of diols and immediate precursors of
amino alcohols like 16.
The asymmetric organocatalyzed aaminoxylation of aldehydes and ketones
is a powerful, metal-free, direct method
for the synthesis of a-hydroxy aldehydes
and ketones. The reaction with nitrosobenzene forms the a-phenylaminoxy
carbonyl both regio- and enantioselectively in good to excellent yields. The
directness of the approach to a-hydroxy
carbonyls, the generality of the prolinemediated nitrosoaldol reaction, which
permits great flexibility in selection of
aldehydes and ketones, and the versa-
Angew. Chem. Int. Ed. 2004, 43, 2995 –2997
[18]
[1] J. Fuhrhop, G. Penalin, Organic Synthesis, 2nd ed., VCH, Weinheim, 1994,
chap. 2.
[2] F. A. Davis, B.-C. Chen, Houben Weyl:
Methods of Organic Chemistry. Stereoselective Synthesis, Vol. E21 (Eds.: G.
Helmchen, R. W. Hoffmann, J. Mulzer,
E. Schaumann), George Thieme, Stuttgart, 1996, pp. 4497 – 4518.
[3] F. A. Davis, B.-C. Chen, Chem. Rev.
1992, 92, 919 – 934.
[4] W. Adam, M. Lazarus, C. R. Saha-MKller, P. Schreier, Acc. Chem. Res. 1999, 32,
837 – 845.
[5] a) S. T. Handy, Curr. Org. Chem. 2000, 4,
363 – 395; b) Special Issue on Enantioselective Synthesis: Chem. Rev. 2003,
103(8), 2761 – 3400.
[6] a) W. Adam, R. T. Fell, V. R. Stegmann,
C. R. Saha-MKller, J. Am. Chem. Soc.
www.angewandte.org
[19]
[20]
[21]
[22]
1998, 120, 708 – 714; b) M. Masui, A.
Ando, T. Shioiri, Tetrahedron Lett. 1988,
29, 2835 – 2838; c) P. Zhou, B.-C. Chen,
F. A. Davis in Asymmetric Oxidation
Reactions (Ed.: T. Katsuki), Oxford
University Press, Oxford, 2001.
R. O. Duthaler, Angew. Chem. 2003,
115, 1005 – 1008; Angew. Chem. Int.
Ed. 2003, 42, 975 – 978.
For reviews on nitroso compounds see:
a) P. Zuman, P. Shah, Chem. Rev. 1994,
94, 1621 – 1641; b) L. Soghyuk, C. Li,
H. W. Ann, Chem. Rev. 2002, 102, 1019 –
1066.
N. Momiyama, H. Yamamoto, Org. Lett.
2002, 4, 3579 – 3582.
N. Momiyama, H. Yamamoto, Angew.
Chem. 2002, 114, 3112 – 3114; Angew.
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Corrigendum: Angew. Chem. 2002, 114,
3459; Angew. Chem. Int. Ed. 2002, 41,
3313.
N. Momiyama, H. Yamamoto, J. Am.
Chem. Soc. 2003, 125, 6038 – 6039.
P. I. Dalko, L. Moisan, Angew. Chem.
2001, 113, 3840 – 3864; Angew. Chem.
Int. Ed. 2001, 40, 3726 – 3748.
B. List, Synlett 2001, 1675 – 1686.
Although the catalyst activity of (S)proline has been known since the 1970s,
it was not applied for asymmetric catalysis until recently. See: M. Movassaghi,
E. N. Jacobsen, Science 2002, 298, 1904 –
1905.
B. List, Tetrahedron 2002, 58, 5573 –
5590.
S. P. Brown, M. P. Brochu, C. J. Sinz,
D. W. C. MacMillan, J. Am. Chem. Soc.
2003, 125, 10 808 – 10 809.
Y. Hayashi, J. Yamaguchi, K. Hibino, M.
Shoji, Tetrahedron Lett. 2003, 44, 8293 –
8296.
G. Zhong, Angew. Chem. 2003, 115,
4379 – 4382; Angew. Chem. Int. Ed.
2003, 42, 4247 – 4250.
In fact, most experiments carried out by
Hayashi and co-workers (see ref. [18])
are conducted in the presence of
30 mol % (S)-proline. Similarly, Zhong
(see ref. [19]) used 20 mol % catalyst.
A. Bøegevig, H. Sunden, A. CMrdova,
Angew. Chem. 2004, 116, 1129 – 1132;
Angew. Chem. Int. Ed. 2004, 43, 1109 –
1112.
Y. Hayashi, S. Yamaguchi, T. Sumiya, M.
Shoji, Angew. Chem. 2004, 116, 1132 –
1135; Angew. Chem. Int. Ed. 2004, 43,
1112 – 1115.
a) S. L. Schreiber, Science 2000, 287,
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2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2997
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asymmetric, aminoxylation, compounds, diols, ketonesчa, amin, hydroxycarbonyl, event, alcohol, aldehyde, efficiency, enantiomerically, organocatalytic, access, pure
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