The direct catalytic asymmetric α-aminooxylation reaction: Development of stereoselective routes to 1,2-diols and 1,2-amino alcohols and density functional calculations

Article abstract of DOI:10.1002/chem.200400137

Proline-catalyzed direct asymmetric α-aminooxylation of ketones and aldehydes is described. The proline-catalyzed reactions between unmodified ketones or aldehydes and nitrosobenzene proceeded with excellent diastereo- and enantioselectivities. In all cases tested, the corresponding products were isolated with > 95% ees. Methyl alkyl ketones were regiospecifically oxidized at the methylene carbon atom to afford enantiomerically pure α-aminooxylated ketones. In addition, cyclic ketones could be α,α′-dioxidized with remarkably high selectivity, furnishing the corresponding diaminooxylated ketones with > 99% ees. The reaction mechanism of the proline-catalyzed direct asymmetric α-aminooxylation was investigated, and we performed density functional theory (DFT) calculations in order to investigate the nature of the plausible transition states further. We also screened other organocatalysts for the asymmetric α-oxidation reaction and found that several proline derivatives were also able to catalyze the transformation with excellent enantioselectivities. Moreover, stereoselective routes for the synthesis of monoprotected vicinal diols and hydroxyketones were found. In addition, short routes for the direct preparation of enantiomerically pure epoxides and 1,2-amino alcohols are presented. The direct catalytic α-oxidation is also a novel route for the stereoselective preparation of β-adrenoreceptor antagonists.

Full text of DOI:10.1002/chem.200400137

FULL PAPER
The Direct Catalytic Asymmetric a-Aminooxylation Reaction:
Development of Stereoselective Routes to 1,2-Diols and
1,2-Amino Alcohols and Density Functional Calculations
Armando CÛrdova,*[a] Henrik Sundÿn,[a] Anders B˘gevig,[a]
Mikael Johansson,[a] and Fahmi Himo[b]
Abstract:
Proline-catalyzed
direct
nishing the corresponding diaminooxy-
lated ketones with >99% ees. The re-
action mechanism of the proline-cata-
lyzed direct asymmetric a-aminooxyla-
tion was investigated, and we per-
formed density functional theory
(DFT) calculations in order to investi-
gate the nature of the plausible transi-
tion states further. We also screened
other organocatalysts for the asymmet-
ric a-oxidation reaction and found that
several proline derivatives were also
able to catalyze the transformation
asymmetric a-aminooxylation of ke-
tones and aldehydes is described. The
proline-catalyzed reactions between
unmodified ketones or aldehydes and
nitrosobenzene proceeded with excel-
lent diastereo- and enantioselectivities.
In all cases tested, the corresponding
products were isolated with >95% ees.
Methyl alkyl ketones were regiospecifi-
cally oxidized at the methylene carbon
atom to afford enantiomerically pure
a-aminooxylated ketones. In addition,
cyclic ketones could be a,a’-dioxidized
with remarkably high selectivity, fur-
with
excellent
enantioselectivities.
Moreover, stereoselective routes for
the synthesis of monoprotected vicinal
diols and hydroxyketones were found.
In addition, short routes for the direct
preparation of enantiomerically pure
epoxides and 1,2-amino alcohols are
presented. The direct catalytic a-oxida-
tion is also a novel route for the stereo-
selective preparation of b-adrenorecep-
tor antagonists.
Keywords: aminooxylations ¥ asym-
metric catalysis ¥ density functional
calculations ¥ proline
Introduction
Optically active a-hydroxy carbonyl moieties are com-
monly found in numerous important natural products and
are highly versatile functional synthons. This has led to ex-
tensive research into finding new diastereoselective and
enantioselective routes for their syntheses.[2] One way of
preparing these compounds is asymmetric a-hydroxylation
of enolates.[3] In addition, nucleophilic additions to chiral
glyoxal derivatives and chiral hydrazones have also been
successfully employed.[2b,c,4] However, these methods are in-
direct and most of them require multiple manipulations for
the desired a-hydroxy product to be obtained. Despite the
extensive research in this area, it was not until recently that
Yamamoto and co-workers reported a more efficient cata-
lytic system based on AgX/binap complexes (binap=2,2’-
bis(diphenylphosphanyl)-1,1’-binaphthyl), which mediate in-
direct a-oxidation of activated tin enolates.[5] The method
was further developed into a one-pot synthesis of a-hydroxy
ketones with high enantioselectivity.
One of the ultimate goals and challenges in chemistry is to
develop stereoselective transformations for the creation of
functionalized optically active molecules displaying structur-
al diversity from simple and easily available starting materi-
als. During the last two decades, the synthesis of enantio-
merically pure or enriched compounds has thus emerged as
one of the most important fields in organic synthesis. Sever-
al procedures to generate optically active molecules are
known and among these, asymmetric catalysis is a highly
active research field.[1]
[a]Prof. Dr. A. CÛrdova, H. Sundÿn, Dr. A. B˘gevig, M. Johansson
Department of Organic Chemistry
The Arrhenius Laboratory
Stockholm University, 106 91 Stockholm (Sweden)
Fax : (+46)815-4908
E-mail: acordova@organ.su.se
Asymmetric reactions catalyzed by metal-free organic cat-
alysts have experienced a renaissance in recent years.[6] In-
terestingly, since the discovery of amino acid catalyzed ster-
eoselective Robinson annulations in the early 1970s,[7] there
acordova1a@netscape.net
[b]Prof. Dr. F. Himo
Department of Theoretical Chemistry
The Royal Institute of Technology
Albanova, 106 91 Stockholm (Sweden)
À
was no intensive research on this concept for other C C
Chem. Eur. J. 2004, 10, 3673 3684
DOI: 10.1002/chem.200400137
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3673

FULL PAPER
bond-forming reactions for several decades, even though the
reaction is frequently used in the preparation of building
blocks for the total synthesis of natural products.[8] It was
not until recently that researchers demonstrated that amino
acid derivatives function as catalysts for direct asymmetric
tion, we believed that the ability of the amino acid to act as
a Br˘nstedt base should favor O- over N-addition.[5,23]
In an initial experiment, we treated cyclohexanone 1a
(10 mmol) with nitrosobenzene 2 (1 mmol) in the presence
of a catalytic amount of (S)-proline (20 mol%) in DMSO
(4 mL) at room temperature [Eq. (2)].
19]
intermolecular reactions.[9
From the elegant work of Yamamoto and co-workers and
our own previous research on direct amine-catalyzed asym-
metric synthesis we saw potential for an amino acid to cata-
lyze a-aminooxylation of unmodified ketones and aldehydes
The initial light blue solution went from light green to
dark green, and finally became orange within 30 minutes.
The reaction was found to be complete, providing not only
ketone 3a in 70% yield and >99% ee, but also the corre-
sponding C2-symmetric a,a’-diaminooxylated ketone 4a in
22% yield and >99% ee.
11k,12a,20]
[Eq. (1)].[9d,f,g,11d
In parallel with this experiment, we also treated hexanal
1b (2 mmol) with 2 (1 mmol) in the presence of a catalytic
amount of (S)-proline (20 mol%), obtaining the correspond-
We thus embarked on the
quest to develop a novel enam-
ine-catalyzed asymmetric route
for the synthesis of a-hydroxy-
containing molecules. We have
recently disclosed the first
direct catalytic a-oxidation of
ketones, yielding protected a-
hydroxy ketones with excellent
regioselectivity and >99% ee.[21]
In this paper, we describe our
findings, including the scope,
mechanism, and applications of
the highly stereoselective a-aminooxylation of unmodified
ketones and aldehydes.
ing a-substituted aldehyde 3b in 61% yield with >99% ee.
The aldehyde adduct 3b was oligomeric in solution and less
stabile than 3a during workup and storage. We therefore de-
cided to reduce 3b in situ with excess NaBH4 to give the
corresponding more stable monoprotected terminal diol
prior to workup and purification.
Results and Discussion
There are only a few reports of indirect reactions with silyl
enol ethers as nucleophiles and nitrosoaromatic compounds
as electrophiles.[22] Most of these reactions furnish the corre-
sponding a-hydroxy amino adducts with excellent N-addi-
tion chemoselectivity. However, Momiyama and Yamamoto
recently demonstrated that the chemoselectivity of the reac-
tion with nitrosobenzene could be switched from N- to O-
addition by performing the transformation in the presence
of a catalytic amount of a Lewis acid.[23] They also expanded
this concept to a catalytic asymmetric system mediated by
AgX/binap complexes; this affords a-aminooxylated ketones
with high chemo- and enantioselectivities.[5]
Donor component: Delighted over these results, we decided
to test the reaction for different ketones and aldehydes
(Tables 1 and 2). A set of different carbonyl donors was
therefore treated just by stirring and mixing of the donor
and nitrosobenzene in the presence of a catalytic amount of
(S)- or (R)-proline in DMSO. Table 1 presents direct catalyt-
ic asymmetric a-oxidations of ketones 1a and 1c i. The re-
actions proceeded smoothly, affording the corresponding a-
aminooxylated ketones 3a and 3c i in good yields and with
>99% ees. In addition, excellent regioselectivities were ob-
served for a-aminooxylation of acyclic ketones, and no
doubly a,a’-diaminooxylated ketones were observed. The
oxidation occurred exclusively on the methylene carbons of
the ketones; protected hydroxy ketone 3 f, for example, was
isolated as a single regioisomer in 70% yield and with
>99% ee. With regards to the O- or N-selectivity of the re-
action, we found that the reaction was chemoselective, fur-
nishing no N-addition products for transformations with cy-
clohexanones as donors.
During our preliminary investigations of direct proline-
catalyzed asymmetric Mannich and aldol reactions with un-
modified ketones and aldehydes we realized the potential of
utilizing this catalytic system for other stereoselective reac-
11k]
tions.[9d,f,i,11d
The basis of the catalytic cycle would be the
ability of a cyclic five-membered secondary amine to form a
chiral enamine and to perform a subsequent nucleophilic
attack on an electrophile in a highly enantioselective fash-
ion. Previous studies by Yamamoto and co-workers had
made us interested in whether enamine catalysis could be
applied in reactions with nitrosoaryl compounds.[5,23] In addi-
a-Oxidation of acyclic ketones, however, afforded small
amounts (<25%) of the corresponding 2-amino ketones 5
with the same regioselectivity as the O-addition adducts and
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Chem. Eur. J. 2004, 10, 3673 3684

Asymmetric a-Aminooxylations
3673 3684
Table 1. Proline-catalyzed direct asymmetric a-aminooxylation of unmodified ketones.[a]
also performed the reaction
with racemic 3-methylcyclohex-
anone as the donor (vide infra),
to obtain regiomers 3e and 3e’
with >99% ee. Interestingly,
(3R,2R)-3-methyl-2-(N-phenyl-
aminoxy) (3e) was formed ex-
clusively as determined by
HPLC and NMR analyses. (S)-
Proline thus reacted more rap-
idly with (3R)- and (2R)-meth-
Entry
1
Donor
Product
Yield [%][b]
70 (99)[d]
3:5
ee [%]of 3[c]
>99 (>99)[d]
ee [%]of 5[c]
>100:1 (100:1)[d]
ylcyclohexanone
than
with
(3S)- and (2S)-methylcyclohex-
anone, respectively. In addition
to a- ketones 3, the reactions
between cyclohexanones with
two a-methylene carbons and 2
provided the corresponding C2-
symmetric a,a’-diketones 4,
each as a single diastereomer
with >99% ee (Scheme 1).
2
71 (94)[d]
>100:1 (100:1)[d]
>100:1 (100:1)[d]
>99 (>99)[d]
3
4
66 (82)[d]
>99 (>99)[d]
>100:1 (100:1)[d]
>100:1 (100:1)[d]
>99 (>99)[d]
>99 (>99)[d]
For example, the protected
dihydroxy ketone 4c was isolat-
ed in 19% yield and with
>99% ee. These types of enan-
tiomerically pure ketones are
generally prepared in six steps
in overall yields of 15 20% and
are useful synthetic building
blocks in natural product
chemistry.[24] The second O-ad-
dition exhibited remarkable
high selectivity, since no meso-
diadduct was detected either by
NMR or by HPLC analyses
during the progress of the reac-
tion. This is the first time that
this type of double stereoselec-
tive nucleophilic attack onto an
electrophile has been reported
in a proline-catalyzed reaction;
this indicates that nitrosoben-
zene is more reactive and/or
provides less steric hindrance
than other electrophiles such as
diazocarboxylates or a-imino-
68 (88)[d]
5
6
93
66
81:19
98:2
>99
11
7
99
7
8
87
64
78:22
90:10
>99
>99
<5
<5
[a]Method A: A mixture of 1 (10 mmol, 10 equiv), 2 (1 mmol) and (S)-proline was stirred at room tempera-
ture for 2 3 h. The crude product obtained after aqueous workup was purified by column chromatography.
[b]Isolated combined yield of 3 and 5 after silica gel column chromatography. [c]Determined by chiral-phase
HPLC analyses. [d]Method B: A mixture of 2 (1 mmol) was added by syringe pump to a vial containing 1
(2 mmol, 2 equiv) and (S)-proline and the reaction mixture was stirred at room temperature for 2 8 h. The
crude product obtained after aqueous workup was purified by column chromatography.
with a minor chiral induction. Furthermore, the sterically
hindered racemic 2-methylcyclohexanone (1d) was also effi-
ciently a-aminooxylated, providing the corresponding keto
adduct 3d as a 3:1 (trans/cis) diastereomeric mixture in
>99% ee (Table 1, entry 3). In this case, excellent O-selec-
tivity was observed, since no N-addition product was
formed. The proline-catalyzed a-oxidation reaction between
(3R)-methylcyclohexanone (1e) and 2 furnished the two re-
giomers 3e and 3e’ as a 1:1 mixture of regioisomers in 68%
combined yield and each with >99% ee. NMR analyses of
3e revealed a cis relationship between the substituents.
Hence, 3e had a (2R,3R) absolute configuration of the
2-oxyaminophenyl group and methyl group, respectively. We
glyoxylates.[12c,11d] We also investigated the possibility of in-
creasing the yield of 3 by slow addition of electrophile 2 to
the reaction mixture by syringe pump. We believed that this
Scheme 1. Direct catalytic asymmetric synthesis of mono- and diprotect-
ed hydroxy ketones.
Chem. Eur. J. 2004, 10, 3673 3684
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3675

A. CÛrdova et al.
FULL PAPER
procedure should reduce the formation of the dioxidized ad-
ducts 4 and dimerization of 2. Indeed, this method signifi-
cantly increased the yield of the a-aminooxylated ketones 3
and allowed for the employment of only two equivalents of
the donor. For example, ketone 3a was isolated in 99%
yield with >99% ee. In addition, we were able to increase
the yield of 4 by subsequent addition of the electrophile 2
by syringe pump to the 3 obtained from the first addition.
The yields of 4a and 4c, for example, were improved to 30
and 25%, respectively, by this process.
>99% ee. The a-oxidation of unsaturated aldehydes can
thus be regarded as a chemo- and regioselective route for
the asymmetric dihydroxylation of olefins.[26] Moreover,
direct catalytic asymmetric a-aminooxylation was also an ef-
ficient route for the synthesis of orthogonally protected
triols (Table 2, entry 5). The reactions with unmodified alde-
hydes were highly chemoselective, and only O-addition was
observed. Moreover, the increased reactivity of the aldehyde
donors in relation to the acyclic ketones allowed us to
employ only 1.5 equivalents of the aldehyde donor without
the need for slow addition of the electrophile to the reaction
mixture.
The direct catalytic asymmetric a-oxidation reactions with
ketones and aldehydes were readily performed on multi-
gram scales in the presence of air. The catalyst loading
could be decreased to as little as 1 mol% without affecting
the yield or enantioselectivity of the a-aminooxylation of
unmodified aldehydes and cyclohexanones (Scheme 3).
Table 2 shows the results of a-oxidations of different un-
modified aldehydes in DMSO. The reactions proceeded
smoothly, affording the corresponding adducts 3b and 3j s
Table 2. Proline-catalyzed direct asymmetric a-aminooxylation of un-
modified aldehydes.[a]
Entry
R
Product Yield[%][b] ee [%]of 3[c]
1
2
3
4
5
6
7
8
nBu
Et
Me
n-pentane
CH2OBn
iPr
CH2CH=CH2
CH2Ph
n-hexane
3b
3j
3k
3l
3m
3n
3o
3p
3q
78
75
79
74
76
74
79
77
76
78
77
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
9
10
11
cis-CH2CH=CH(CH2)5CH3 3r
cis-(CH2)4CH=CHCH2)CH3 3s
Scheme 3. Direct catalytic asymmetric a-aminooxylation reactions with
1 mol% (S)-proline.
[a]Experimental procedure:
a
mixture of
1
(2 mmol, 2 equiv), 2
(1 mmol) and (S)-proline was stirred at room temperature for 2 3 h and
the aldehyde products 3 were reduced in situ to the corresponding alco-
hols. The crude products obtained after aqueous workup were purified
by column chromatography. [b]Isolated yield of the corresponding alco-
hol after silica gel column chromatography. [c]The enantiomeric excesses
were determined by chiral-phase HPLC analyses of the corresponding al-
cohol adducts.
In addition, the progress of the reaction could be simply
monitored by the human eye, since the reaction mixture
switches color from light blue to green and finally to orange,
which indicates that the reaction has been completed.
Solvent: We also performed a solvent screen of the direct
catalytic asymmetric a-aminooxylation of ketone 1a and al-
dehyde 1b. Proline-catalyzed direct asymmetric a-aminoox-
ylations between 1a and 2 were successful in all solvents
tested, affording 3a with excellent enantioselectivity
(Table 3).
The highest reactivity was observed in DMSO, followed
by CHCl3, CH3CN, DMF, and N-methylpyrrolidone (NMP).
Interestingly, the formation of 4a was solvent-dependent.
For example, the reaction in CHCl3 only afforded 3a, which
was isolated in 91% yield with >99% ee. However, 4a was
formed in DMSO, DMF, NMP, and CH3CN. In addition, the
direct catalytic a-aminooxylation of acyclic ketones only
provided insignificant amounts of adducts 3 in CHCl3. Nota-
bly, slow addition of the electrophile 2 to the reaction mix-
ture by syringe pump significantly increased the yield of 3,
which was isolated in 99% yield and >99% ee in DMF,
CH3CN, and DMSO. Furthermore, the reaction could toler-
ate up to 10% water without its yield and ee being affected
(Table 3, entry 11).
with >99% ees. The a-aminooxylated aldehyde adducts are
important synthons, and the mild reaction conditions al-
lowed for a variety of aldehydes with functional groups to
be used. For example, aldehyde adduct 3r is a key inter-
mediate in the syntheses of leukotrienes and isoprostanes.[25]
The aldehydes were reduced in situ, yielding the corre-
sponding more stable monoprotected terminal diols 6b and
6j s without loss of stereoselectivity (Scheme 2).
The unsaturated diols 6o, 6r, and 6s, for instance, were
isolated in 79, 78, and 77% yields, respectively, each with
Scheme 2. One-pot catalytic asymmetric synthesis of monoprotected ter-
minal diols.
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Chem. Eur. J. 2004, 10, 3673 3684

Asymmetric a-Aminooxylations
3673 3684
Table 3. Solvent screen of the proline-catalyzed a-aminooxylation of unmodified ketones.[a]
Catalyst: We also screened dif-
ferent organic amines as poten-
tial catalysts for the direct
asymmetric a-aminooxylation
reaction (Table 5). Of the limit-
[b]
ee [%]of 3[c]
ee [%]of 4[c]
ed
number
of
catalysts
Entry
Solvent
t [h]
T [8C]Yield [%]
3:4
screened, proline and hydroxy-
proline derivatives provided
enantiomerically pure 3a. In
addition, all the successful cata-
lysts afforded product 3a with
the same absolute configura-
tion, as determined by optical
rotation and chiral HPLC anal-
yses. Ether- and amine-func-
tionalized pyrrolidine deriva-
tives provided 3a in trace
amounts, establishing the im-
1
2
3
4
5
6
7
8
DMSO
DMSO
DMF
3
5
8
16
6
5
RT
RT
RT
4
RT
RT
RT
RT
RT
RT
RT
92
3:1
>99
>99[d]
>99
>99[d]
>99
>99
>99
99
>99
n.d.[d]
>99
n.d.[d]
n.d.
n.d.
>99
n.d.
99[d]
68
>20:1[d]
10:1
DMF
99[d]
66
91
65
45
41
25
91
>20:1[d]
19:1
>20:1
10:1
>20:1
>20:1
>20:1
3:1
CH3CN
CHCl3
NMP
THF
dioxane
Et2O
8
16
16
17
3
9
10
11
99
99
>99
n.d.
n.d.
>99
DMSO/H2O 9:1
[a]Reaction conditions: see Method A in the Experimental. [b]Isolated combined yield of 3a and 4a after
silica gel column chromatography. [c]Determined by chiral-phase HPLC analyses. [d]Reactions performed ac-
cording to Method B in the Experimental Section.
The solvent screen of the reaction with hexanal revealed
that the best solvents for obtaining 3b with high enantiose-
lectivity were DMSO, DMF, CH3CN, and CHCl3 (Table 4).
In particular, the reactions in DMSO and DMF proceeded
Table 4. Solvent screen of the proline-catalyzed a-aminooxylation of un-
modified aldehydes.[a]
portance of the carboxyl group and its acidic proton. Inter-
estingly, pipecolinic acid was not a catalyst for the reaction,
confirming the significance of the cyclic five-membered sec-
ondary amine structural motif for achievement of high enan-
tioselectivity. Similar observations have also been made in
amine-catalyzed direct asymmetric aldol and Mannich reac-
tions.[9a,b,11f]
[b]
Entry
Solvent
t [h]
T [8C]Yield [%]
ee [%]of 3b[c]
1
2
3
4
5
6
7
8
DMSO
DMSO
DMF
17
0.7
16
17
2h
16
24
0.7
17
16
17
RT
RT
RT
RT
4
92
64
70
24
42
50
86
64
40
>99
>99
>99
99
97
93
95
93
97
96
Stereoselective synthesis of chiral synthons: The a-amino-
oxylated aldehydes and ketones are valuable synthetic inter-
mediates. For instance, we developed an efficient synthesis
of vicinal diols (Scheme 4).
Hence, monoprotected diols 6 were derived through one-
pot sequential catalytic asymmetric a-aminooxylation re-
duction reactions of the unmodified aldehydes and ketones.
Subsequent removal of the aniline by hydrogenolysis (PtO2
CH3CN
CH3CN
CH3CN
CH3CN
CHCl3
CHCl3
CHCl3
dioxane
4
À20
4
9
10
11
RT
4
RT
48
traces
n.d.
Adams× catalyst, H2) or with
a catalytic amount of
[a]Reaction conditions: See Experimental Section. [b]Isolated combined
yield of the corresponding alcohol 6b after silica gel column chromatog-
raphy. [c]Determined by chiral-phase HPLC analyses of the correspond-
ing alcohol 6b.
CuSO4¥5H2O furnished the corresponding enantiomerically
pure diols 7. For example, enantiomerically pure diol (À)-
7n was isolated from the (R)-proline-catalyzed reaction be-
tween isovaleraldehyde and 2 in 73% yield, over two steps
(Scheme 4a). Determination of the optical rotation and
comparison to the literature revealed that the direct catalyt-
ic asymmetric a-aminooxylations of aldehydes catalyzed by
(S)-proline and by (R)-proline afforded (2R)-1,2-diols and
(2S)-1,2-diols, respectively.[27] The catalytic asymmetric a-
aminooxylation reduction sequence was also investigated
with unmodified 1a as the donor. Hence, (S)-proline-derived
a-amino hydroxy ketone 3a was readily reduced in situ with
NaBH4 to the corresponding monoprotected diol 6a, which
was isolated in 88% yield, over the two steps, with a dr of
2:1 (trans/cis) and >99% ee (Scheme 4b). Removal of the
aniline with Adams× catalyst and H2 or catalytic CuSO4 fur-
with almost absolute stereocontrol. The enantioselectivity of
the a-aminooxylation of 1b was slightly lower in other sol-
vents, in which 3b was furnished with 93 99% ees. The
enantioselectivity of the direct a-aminooxylation of alde-
hydes was thus affected slightly by the solvent used as com-
pared to the a-aminooxylation of unmodified ketones. Inter-
estingly, the best solvent for a-aminooxylation of 2-substitut-
ed acetaldehydes was CH3CN. The proline-catalyzed asym-
metric a-aminooxylation of 2-phenylacetaldehyde (1t) with
2 at À208C, for example, furnished the corresponding alco-
hol 6t after in situ reduction with NaBH4 in 79% yield with
an ee of 99% [Eq. (3)].
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A. CÛrdova et al.
FULL PAPER
Table 5. Catalyst screen.[a]
tion of all the possible stereoisomers of chiral 1,2-diols. In
addition, the direct catalytic asymmetric a-aminooxylation
of aldehydes and ketones can be regarded as an alternative
to Sharpless asymmetric dihydroxylation.[26]
The catalytic a-aminooxylation of unmodified ketones 1
could also be readily combined in one-pot fashion with
CuSO4-mediated aniline removal of the ketone adducts 3
generated in situ, which afforded a-hydroxy and a,a’-dihy-
droxy ketones without loss of stereoselectivity. For example,
3a was converted into the corresponding optically pure a-
hydroxy ketone adduct (2R)-8a in 92% yield [Eq. (4)].[5,29]
Entry
1
Catalyst
Yield [%][b]
70
ee [%][c]
>99
2
64
>99
3
3
4
66
67
>99
>99
n.d.
trace
Determination of the optical rotations of 7a and 8a and
comparison with the literature revealed that a-aminooxyla-
tion of unmodified ketones catalyzed by (S)-proline afford-
ed (2R)-a-ketones and (R)-a-hydroxy ketones, respective-
ly.[28,29] In accordance, (S)-proline also catalyzed the forma-
tion of C2-symmetric (2R,6R)-a,a’-diketones and (2R,6R)-
a,a’-dihydroxy ketones.
We also investigated the possibility of utilizing the direct
catalytic asymmetric a-aminooxylation as a direct route for
the catalytic asymmetric syntheses of epoxides and 1,2-
amino alcohols (Scheme 5).
6
7
trace
trace
n.d.
n.d.
[a]Reaction conditions: see Method A in the Experimental. [b]Isolated
yield of 3a after silica gel column chromatography. [c]Determined by
chiral-phase HPLC analyses.
Chiral 1,2-amino alcohols are
important structural elements
in chiral ligands for asymmetric
catalysis as well as biologically
active compounds (e.g., b-adre-
nergic receptor blockers and
immune stimulants).[30,31]
For example, the enantiomer-
ically pure alcohols ent-6p and
ent-6t obtained from (R)-pro-
line catalysis were efficiently
converted into the correspond-
ing epoxides 9p and 9t in 83%
and 81% yields, respectively,
each with an ee of >99%. The
direct catalytic asymmetric a-
oxidation can thus be regarded
as an efficient route for the
stereoselective synthesis of ep-
oxides. The regioselective ring-
Scheme 4. Direct catalytic asymmetric synthesis of vicinal diols. a) i) (S)-proline, DMSO, RT; ii) NaBH4,
MeOH/DMSO, RT; b) (R)-proline, DMSO, RT; ii) NaBH4, MeOH/DMSO, RT, c) Adams× catalyst (PtO2), H2,
MeOH, RT; d) CuSO4¥5H2O, MeOH, 08C.
opening of 9t with NaN3 ac-
cording to literature proce-
dures, followed by hydrogena-
nished the known (1S,2S)-trans-1,2-cyclohexanediol (7a)
and cis-1,2-cyclohexanediol in 96% combined yield, with
>99% ee for the optically active diol.[28] As selective reduc-
tion of a-hydroxy ketones to both syn- and anti-1,2-diols are
known, this procedure is one practical route for the prepara-
tion of the corresponding azide with Adams× catalyst, af-
forded 10t or 11t in 91% and 92% yields, respectively.[32]
The 1-isopropylamino-2-alcohol structural motif of com-
pound 11t is the core moiety of b-adrenoreceptor antago-
nists,[33] and so the direct catalytic asymmetric a-aminooxy-
3678
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Chem. Eur. J. 2004, 10, 3673 3684

Asymmetric a-Aminooxylations
3673 3684
Scheme 5. Asymmetric synthesis of epoxides and 1,2-amino alcohols.
lation can also be viewed as a novel synthetic route for the
preparation of antihypertensive drugs (b-blockers). Impor-
tantly, employment of (R)-proline catalysis afforded the
active S enantiomers of the drugs.
Figure 1. Linear effect in the (S)-proline-catalyzed a-aminooxylation of
cyclohexanone with nitrosobenzene in DMSO (y=0.99x+0.70, R2 =
0.998).
Mechanism: The mechanism of the proline-catalyzed direct
asymmetric a-aminooxylation reactions is depicted in
Scheme 6. Accordingly, the aldehyde donor reacts with pro-
line, resulting in an enamine. Next, the nitrosobenzene 2
reacts with the enamine to give (after hydrolysis) the enan-
tiomerically pure a-adduct and the catalytic cycle can be re-
peated.
regio- and enantioselectivities of the a-aminooxylation reac-
tions of unmodified aldehydes and ketones, respectively
(Figure 2). Hence, (S)-proline forms an enamine with the al-
dehyde or ketone, and this is attacked from its si face, pro-
viding (2R)-a-aminooxylated aldehydes and ketones, re-
spectively. The six-membered metal-free Zimmermann
Traxler transition state is stabilized by hydrogen bonding be-
tween the nitrogen of the nitrosobenzene and the carboxylic
acid group of proline. We have performed density functional
theory (DFT) calculations to investigate the nature of these
transition states further. In the calculations, the phenol ring
of the nitrosobenzene was modeled with a suitable methyl
group. The optimized transition state geometries corre-
sponding to structures I IV in Figure 2 are displayed in
Figure 3.
The main result from the calculations is that TS-I and TS-
III were found to have energies 6.6 and 7.2 kcalmolÀ1 lower
than TS-II and TS-IV, respectively. This explains the excep-
tionally high stereoselectivity observed for the reaction. The
À
O C bond to be formed is shorter (ca. 0.2 ä) in TS-I and
À
TS-III than in the corresponding TS-II and TS-IV. The N H
Scheme 6. The mechanism of the proline-catalyzed direct catalytic a-ami-
nooxylation of unmodified aldehydes and ketones.
bond length is also quite short in all transition state struc-
tures: 1.08 1.16 ä. We have also performed calculations to
test the reaction mechanism proposed by MacMillan and co-
We did not observe any non-
linear effect in the proline-cata-
lyzed reaction (Figure 1),[34] so
it is likely that a single proline
molecule is involved in the
transition state and mechanism,
acting as a molecular robot/
enzyme (Figure 2).
From the absolute configura-
tion, which is opposite to that
of the adducts 3 derived from
Yamamoto×s reaction,[5] we pro-
pose transition state models I
and III to account for the
Figure 2. Plausible transition states for the (S)-proline-catalyzed reactions.
www.chemeurj.org ¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2004, 10, 3673 3684
3679

A. CÛrdova et al.
FULL PAPER
calculations, the mechanism and transition state models of
the catalytic asymmetric a-oxidations are discussed. Taken
as a whole, the reported transformation should be an inex-
pensive and useful route for the synthesis of optically active
alcohol and amino alcohol molecules.
Experimental Section
General methods: Chemicals and solvents were either purchased puriss
p. A. from commercial suppliers or were purified by standard techniques.
For thin layer chromatography (TLC), Merck 60 F254 silica gel plates
were used and compounds were viewed by irradiation with UV light and/
or by treatment with
a solution of phosphomolybdic acid (25 g),
Ce(SO4)2¥H2O (10 g), conc. H2SO4 (60 mL), and H2O (940 mL) followed
by heating or by treatment with a solution of p-anisaldehyde (23 mL),
conc. H2SO4 (35 mL), acetic acid (10 mL), and ethanol (900 mL) and sub-
sequent heating. Flash chromatography was performed on Merck 60
silica gel (particle size 0.040 0.063 mm). 1H NMR and 13C NMR spectra
were recorded on a Varian AS 400 instrument. Chemical shifts are given
in d relative to tetramethylsilane (TMS); the coupling constants (J) are
given in Hz. The spectra were recorded in CDCl3 or CD3OD as solvents
1
at room temperature, TMS served as internal standard (d=0 ppm) for H
NMR, and CDCl3 was used as internal standard (d=77.0 ppm) for 13C
NMR. HPLC was carried out on a Hitachi organizer consisting of a D-
2500 Chromato-Integrator, an L-4000 UV-Detector, and a L-6200A Intel-
ligent Pump, and a Waters 2690 Millennium with photodiode array detec-
tor. Optical rotations were recorded on a Perkin Elmer 241 Polarimeter
(l=589 nm, 1 dm cell). High-resolution mass spectra were recorded on
an IonSpec FTMS mass spectrometer with a DHB-matrix.
Figure 3. DFT-optimized transition state geometries, corresponding to
structures I IV in Figure 2.
workers.[20b] Every attempt to
optimize the key transition state
of that mechanism (TS-V in
Figure 4) resulted in a structure
very similar to that of TS-I.
Typical experimental procedure for the direct a-aminooxylation of ke-
tones (Method A): The ketone (10 equiv) was added to a vial containing
nitrosobenzene (1 mmol) and
a catalytic amount of (S)-proline
(20 mol%) in DMSO (4 mL). The reaction was quenched after 2 3 h of
vigorous stirring by addition of aqueous NH4Cl. The aqueous phase was
extracted three times with EtOAc. The combined organic layers were
dried with MgSO4, which was subsequently removed by filtration. The
solvent was removed under reduced pressure after purification of the
crude product mixture by silica gel column chromatography (EtOAc/pen-
tane 1:8) to afford the corresponding a-ketone 3. The ees of the ketones
were determined by chiral-phase HPLC analysis (Daicel AD column, l=
244 nm, v=0.5 mLminÀ1, Hex/IPA).
Figure 4. Plausible
transition
state V.
Conclusion
Typical experimental procedure for the direct a-oxidation of ketones
(Method B): A solution of nitrosobenzene in DMSO (1m, 1 mL) was
added by syringe pump (0.2 mLhÀ1) to a vial containing the ketone
(2 equiv) and a catalytic amount of (S)-proline (20 mol%) in DMSO
(4 mL). The reaction was quenched after 5 7 h of vigorous stirring by ad-
dition of aqueous NH4Cl. The aqueous phase was extracted three times
with EtOAc. The combined organic layers were dried with MgSO4, which
was subsequently removed by filtration. The solvent was removed under
reduced pressure after purification of the crude product mixture by silica
gel column chromatography (EtOAc/pentane 1:8) to afford the corre-
sponding a-aminooxylated ketone 3. The ees of the ketones were deter-
mined by chiral-phase HPLC analysis (Daicel AD column, l=244 nm,
v=0.5 mLminÀ1).
Novel direct catalytic enantioselective a-aminooxylations of
ketones and aldehydes have been described. The stereose-
lective reactions between unmodified ketones or aldehydes
with nitrosobenzene are new starting points for the chemo-,
regio-, and enantioselective syntheses of either enantiomer
of enantiomerically pure 1,2-diols, 1,2-amino alcohols, epox-
ides, and a-hydroxy ketones. In most cases, the reaction pro-
ceeds with absolute stereocontrol. The novel direct a-amino-
oxylation furnishes b-adrenoreceptor antagonists with
>99% ees. In addition, reactions with a-unsubstituted cyclic
ketones as donors in DMSO were remarkably selective, af-
fording the corresponding C2-symmetric a,a’-diketones with
>99% ees. The direct catalytic asymmetric reactions are
readily scaled up, operationally simple, and do not require
an inert atmosphere. In addition, the reactions could be con-
ducted in up to 10% water without loss of enantioselectivity.
The reaction was also catalyzed by other proline derivatives
with excellent stereoselectivity. The reaction does not dis-
play nonlinear effects and so only one proline molecule was
involved in the transition state. From the stereochemistry of
the a-aminooxylated adducts and functional density theory
(2R)-2-(N-Phenylaminooxy)cyclohexanone (3a): [a]D =+111.3 (c=0.15
1
in CHCl3); H NMR (CDCl3): d=1.71 1.79 (m, 4H; CH2CH2CH2), 2.00
2.02 (m, 2H; CH2CH2CH), 2.34 2.48 (m, 2H; CH2CH2CO), 4.35 (q, J=
6.0 Hz, 1H; CHONHAr), 6.94 (t, J=8.1 Hz, 3H; ArH), 7.25 (t, J=
8.4 Hz, 2H; ArH), 7.82 ppm (brs, 1H; ONHAr); 13C NMR: d=d=23.7,
27.2, 32.5, 40.8, 86.2, 114.3, 122.0, 128.8, 148.0, 209.9 ppm; MALDI-TOF
MS: m/z calcd for C12H15NO2: 228.100; found: 228.101 [M+Na]+; ele-
mental analysis calcd (%) for C12H15NO2: C 70.22, H 7.37, N 6.86; found:
C 70.22, H 7.41, N 6.90; HPLC (hexanes/iPrOH 90:10): major isomer:
tR =30.31 min; minor isomer: tR =25.79 min.
(7R)-7-(N-Phenylaminooxy)-1,4-dioxaspiro[4,5]decan-8-one (3c): [a]D =
+65.6 (c=2.45 in CHCl3); 1H NMR (CDCl3): d=1.97 2.05 (m, 2H;
CH2), 2.20 (t, J=0.04 Hz, 1H; CH2), 2.38 2.52 (m, 2H; CH2), 2.61 2.74
(m, 1H; CH2), 4.14 4.00 (m, 4H; OCH2CH2O), 4.65 (dd, J=0.04 Hz,
3680
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chem. Eur. J. 2004, 10, 3673 3684

Asymmetric a-Aminooxylations
3673 3684
0.02 Hz, 1H; CHONHAr), 6.93 (t, J=8.1 Hz, 3H; ArH), 7.25 (t, J=
8.4 Hz, 2H; ArH), 7.83 ppm (brs, 1H; ONHAr); 13C NMR: d=34.4,
36.0, 39.7, 64.8, 64.9, 82.7, 107.6, 114.5, 122.1, 128.9, 148.0, 208.7 ppm;
MALDI-TOF MS: m/z calcd for C14H17NO4: 228.1055; found: 286.106
[M+Na]+; HPLC (hexanes/iPrOH 90:10): major isomer: tR =78.72 min;
minor isomer: tR =68.57 min.
CHONHAr), 6.94 (m, 6H; ArH), 7.24 ppm (m, 4H; ArH); 13C NMR:
d=18.9, 32.6, 85.5, 115.2, 122.9, 129.2, 147.9, 208.9 ppm; MALDI-TOF
MS: m/z calcd for C18H20N2O3: 335.137; found: 335.133 [M+Na]+; HPLC
(hexanes/iPrOH 90:10): major isomer: tR =52.87 min; minor isomer: tR =
49.33 min.
(7S,9S)-7,9-Bis(N-phenylaminooxy)-1,4-dioxa-spiro[4,5]decan-8-one (4c):
[a]D =+42.1 (c=1.85 in CHCl3); 1H NMR (CDCl3): d=2.40 (s, 4H;
CHCH2CH), 4.10 (s, 4H; O(CH2)2O), 4.78 (t, J=0.02 Hz, 2H; CHON-
HAr), 6.95 (m, 6H; ArH), 7.25 ppm (m, 4H; ArH); 13C NMR: d=36.1,
61.2, 78.0, 103.4, 111.2, 118.9, 125.2, 144.0, 203.0 ppm; MALDI-TOF MS:
m/z calcd for C20H22N2O5: 393.1426; found: 393.1424 [M+Na]+; HPLC
(hexanes/iPrOH 90:10): major isomer: tR =161.98 min; minor isomer:
tR =138.33 min.
(2R)-2-Methyl-(6R)-(N-phenylaminooxy)cyclohexanone (3d): [a]D =
+99.6 (c=0.5 in CHCl3); 1H NMR (CDCl3): d=1.10 (d, J=6.3 Hz, 3H;
CH3), 1.51 (m, 2H; CH2CH2CH2), 1.71 (m, 2H; CH2CH), 2.01 (m, 2H;
CH2CH), 2.87 (m, 1H; CHCH3), 4.35 (m, 1H; CHONHAr), 6.94 (m,
3H; ArH), 7.25 (m, 2H; ArH), 7.28 ppm (brs, 1H; ONHAr); 13C NMR:
d=15.3, 20.0, 32,7, 35.7, 43.0, 85.0, 114.9, 122.7, 129.2, 148.3, 213.1 ppm;
MALDI-TOF MS: m/z calcd for 242.116: C13H17NO2; found: 242.116
[M+Na]+; HPLC (hexanes/iPrOH 98:2): major isomer: tR =46.11 min;
minor isomer: tR =38.72 min.
Typical experimental procedure for the direct a-aminooxylation of alde-
hydes and synthesis of 2-aminooxylated alcohols: The aldehyde (2 equiv)
was added at room temperature to a vial containing nitrosobenzene
(1 mmol) and a catalytic amount of (S)-proline (10 mol%) in DMSO
(5 mL). After 2 3 h reaction time, the temperature was lowered to 08C,
followed by dilution with anhydrous MeOH (2.0 mL) and careful addi-
tion of excess NaBH4 (0.25 g). The reaction was quenched after 10 min-
utes by pouring of the reaction mixture into a vigorously stirred biphasic
solution of Et2O and aqueous HCl (1m). The organic layer was sepa-
rated, and the aqueous phase was extracted thoroughly with ethyl ace-
tate. The combined organic phases were dried (MgSO4), concentrated,
and purified by flash column chromatography (silica gel, mixtures of hex-
anes/ethyl acetate) to afford the desired a-alcohols. The ees of the alco-
hols 6 were determined by chiral-phase HPLC analyses (Daicel AD
column, l=244 nm, v=0.5 mLminÀ1).
(3R,2R)-3-Methyl-2-(N-phenylaminooxy)cyclohexanone (3e): [a]D =
+62.6 (c=0.8 in CHCl3); 1H NMR (CDCl3): d=1.01 (d, J=6.8 Hz, 3H;
CH3), 1.91 (m, 4H; RCH2CH2R), 2.35 (m, 1H; CH2CH2CO), 2.51 (m,
1H; CH2CH2CO), 2.63 (m, 1H; CHCH3), 4.42 (dd, J=4.9, 0.8 Hz, 1H;
CHONHAr), 6.94 (m, 3H), 7.25 (m, 2H), 7.51 ppm (brs, 1H; ONHAr);
13C NMR: d=14.0, 23.3, 30.2, 31.1, 37.2, 40.1, 89.5, 114. 7, 122.4, 129.1,
148.3, 210.7 ppm; MALDI-TOF MS: m/z calcd for C13H17NO2: 219.1259;
found: 219.1260 [M]+; HPLC (hexanes/iPrOH 98:2 for 5 min, then gradi-
ent up to 90:10): major isomer: tR =39.12 min; minor isomer: tR =
21.2 min.
(3R,6R)-3-Methyl-(6R)-(N-phenylaminooxy)cyclohexanone (3e’): [a]D =
+67.2 (c=0.9 in CHCl3); 1H NMR (CDCl3): d=1.05 (d, J=8.4 Hz, 3H;
CH3), 1.47 (m, 1H; CH2), 1.77 (m, 1H; CH2), 1.81 (m, 1H; CH2), 2.14
(dd, J=15.8, 0.8 Hz; CH2), 2.46 (m, 3H; CHCH2CO, CHCH3), 4.61 (dd,
J=8.2, 0.04 Hz, 1H; CHONHAr), 6.95 (m, 3H), 7.25 (m, 2H), 8.01 ppm
(brs, 1H; ONHAr); 13C NMR: d=22.2, 31.3, 32.6, 35.3, 49.1, 86.1, 114.6,
122.3, 129.1, 148.2, 209.4 ppm; MALDI-TOF MS: m/z calcd for
C13H17NO2: 219.1259; found:219.1260 [M]+; HPLC (hexanes/iPrOH 98:2
for 5 min, then gradient up to 90:10): major isomer: tR =37.05 min; minor
isomer: tR =20.2 min.
(2R)-2-(N-Phenylaminooxy)hexan-1-ol (6b): [a]D =+22.1 (c=0.8 in
CHCl3); 1H NMR (CDCl3): d=0.92 (t, J=7.2 Hz, 3H; CH3), 1.22 1.75
(m, 6H; CH2CH2CH2), 3.78 (m, 2H; CH2OH), 3.94 (dq, J=6.1, 2.4 Hz,
1H; CHONHAr), 6.94 (m, 3H; ArH), 7.25 (m, 2H; ArH), 7.32 ppm
(brs, 1H; ONHAr); 13C NMR: 14.1, 22.9, 27.9, 29.7, 65.5, 83.9, 114.8,
122.4, 128.9, 148.2 ppm; MALDI-TOF MS: m/z calcd for C12H20NO2
210.1494; found: 210.1491 [M]+; HPLC (hexanes/iPrOH 98:2): major
isomer: tR =32.4 min; minor isomer: tR =27.4 min.
(3R)-3-(N-Phenylaminooxy)butane-2-one (3 f): [a]D =+62 (c=2.3 in
1
CHCl3); H NMR (CDCl3): d=1.14 (d, J=6.4 Hz, 3H; CH3), 2.21 (s, 3H;
(2S)-2-(N-Phenylaminooxy)hexan-1-ol (ent-6b): This product was ob-
tained from (R)-proline catalysis. [a]D =À22.0 (c=0.7 in CHCl3); HPLC
(hexanes/iPrOH 98:2): major isomer: tR =27.4 min; minor isomer: tR =
32.4 min.
CH3), 4.44 (q, 1H; CHONHAr), 6.94 (m, 3H; ArH), 7.25 (m, 2H; ArH),
7.34 ppm (brs, 1H; ONHAr); 13C NMR: d=15.8, 25.9, 84.75, 114.8,
122.7, 129.2, 148.1, 209.4 ppm; MALDI-TOF MS: m/z calcd for
C10H13NO2: 202.084; found: 202.087 [M+Na]+; HPLC (hexanes/iPrOH
99:1): major isomer: tR =97.11 min; minor isomer: tR =72.62 min.
(2R)-(N-Phenylaminooxy)butan-1-ol (6j): [a]D =+20.5 (c=0.7 in
CHCl3); 1H NMR (CDCl3): d=0.96 (t, J=6.9 Hz, 3H; CH3), 1.35 1.75
(m, 2H; CH3CH2CH), 3.78 (m, 2H; CHCH2OH), 3.94 (dq, 1H, J=6.6,
2.6 Hz, CHONHAr), 6.95 (m, 3H; ArH), 7.25 (m, 2H; ArH), 7.32 ppm
(brs, 1H); 13C NMR: d=14.3, 30.7, 65.5, 83.9, 114.8, 122.4, 128.9,
148.2 ppm; MALDI-TOF MS: m/z calcd for C10H15NO2 181.1103; found:
181.1106 [M]+; HPLC (hexanes/iPrOH 98:2): major isomer: tR =
35.4 min; minor isomer: tR =26.4 min.
(2R)-2-(N-Phenylaminooxy)pentane-3-one (3g): [a]D =+57.7 (c=2.1 in
CHCl3); 1H NMR (CDCl3): d=1.11 1.72 (t, J=7.1 Hz, 3H; CH3CH2),
1.43 (d, J=6.0 Hz, 3H; CHCH3), 2.55 (m, 2H; CH2CH3), 4.48 (q, J=
7.1 Hz, 1H; CHONHAr), 6.94 (m, 3H; ArH), 7.25 (m, 2H; ArH),
7.32 ppm (brs, 1H; ONHAr); 13C NMR: d=7.3, 15.9, 31.5, 84.1, 114.5,
122.8, 131.1, 147.9, 211.7 ppm; MALDI TOF-MS: m/z calcd for
C11H15NO2: 216.100; found: 216.098 [M+Na]+; HPLC (hexanes/iPrOH
98:2): major isomer: tR =34.01 min; minor isomer: tR =40.1 min.
(2R)-2-(N-Phenylaminooxy)propan-1-ol (6k): [a]D =+1.21 (c=0.8 in
CHCl3); 1H NMR (CDCl3): d=1.25 (t, J=6.0 Hz, 3H; CH3), 3.77 (m,
2H; CH2OH), 4.12 (m, 1H; CHONHAr), 6.95 (m, 3H; ArH), 7.25 ppm
(m, 2H; ArH); 13C NMR: d=15.5, 66.5, 80.0, 114.6, 122.3, 128.9,
148.3 ppm; MALDI-TOF MS: m/z calcd for C11H18NO2: 168.1024;
found: 168.1023 [M]+; HPLC (hexanes/iPrOH 95:5): major isomer: tR =
17.1 min; minor isomer: tR =14.4 min.
(3R)-3-(N-Phenylaminooxy)hex-5-en-2-one (3h): [a]D =+88.6 (c=3.0 in
CHCl3); 1H NMR (CDCl3): d=2.11 (s, 3H; CH3), 2.39 (m, 2H;
CHCH2CH), 4.41 (q, J=7.1 Hz, 1H; CHONHAr), 5.22 (m, 2H; CH=
CH2), 5.91 (m, 1H; CH=CH2), 6.94 (m, 3H; ArH), 7.25 (m, 2H; ArH),
7.32 ppm (brs, 1H; ONHAr); 13C NMR: d=26.8, 35.1, 88.2, 114.9, 118.8,
122.8, 128.5, 129.2, 135.9, 148.0, 208.4 ppm; MALDI-TOF MS: m/z calcd
for C12H15NO2: 228.100; found: 228.105 [M+H]+; HPLC (hexanes/iPrOH
98:2): major isomer: tR =44.57 min; minor isomer: tR =38.0 min.
(2R)-2-(N-Phenylaminooxy)heptan-1-ol (6l): [a]D =+19.7 (c=4.3 in
CHCl3); 1H NMR (CDCl3): d=0.91 (t, J=7.2 Hz, 3H; CH3), 1.22 1.54
(m, 7H; CH2CH2CH2), 1.68 (m, 1H; CH2CH2CH2), 3.76 (dd, J=12.0,
6.4 Hz, 1H; CH2OH), 3.86 (dd, J=12.1, 2.6 Hz, 1H; CH2OH), 3.94 (m,
1H; CHONHAr), 6.94 (m, 3H; ArH), 7.25 ppm (m, 2H; ArH); 13C
NMR: d=14.2, 22.8, 25.6, 30.1, 32.2, 65.5, 84.2, 115.1, 122.6, 129.2,
148.7 ppm; MALDI-TOF MS: m/z calcd for C13H21NO2: 223.1572;
found: 223.1576 [M]+; HPLC (hexanes/iPrOH 98:2): major isomer: tR =
31.4 min; minor isomer: tR =26.4 min.
(3R)-4-Methyl-(3-N-phenyl-aminooxy)pentan-2-one (3i): [a]D =+94.1
(c=3.5 in CHCl3); 1H NMR (CDCl3): d=1.03 (d, J=7.1 Hz, 3H; CH3),
1.15 (d, J=6.9 Hz, 3H; CH3), 2.14 (m, 1H; CH(CH3)2), 2.18 (s, 3H;
CH3CO), 4.17 (d, J=7.1 Hz, 1H; CHONHAr), 6.94 (m, 3H; ArH), 7.25
(m, 2H; ArH), 7.28 ppm (brs, 1H; ONHAr); 13C NMR: d=17.8, 19.7,
27.0, 30.1, 93.5, 114.9, 122.7, 129.2, 148.3, 209.4 ppm; MALDI-TOF MS:
m/z calcd for C12H17NO2: 230.116; found: 230.118 [M+Na]+; HPLC (hex-
anes/iPrOH 98:2): major isomer: tR =45.72 min; minor isomer: tR =
26.37 min.
(2R)-3-Benzyloxy-2-(N-phenylaminooxy)propan-1-ol (6m): [a]D =+3.4
(c=0.2 in CHCl3); 1H NMR (CDCl3): d=3.77 (m, 2H; CH2OH), 3.90
(m, 2H; BnOCH2), 4.12 (m, 1H; CHONHAr), 4.56 (s, 2H; OCH2Ph),
6.96 (m, 3H; ArH), 7.25 (m, 2H; ArH), 7.33 ppm (m, 5H); 13C NMR:
d=62.8, 69.4, 73.6, 82.5, 114.6, 122.3, 127.5, 127.6, 128.4, 128.9, 137.9,
148.3 ppm; MALDI-TOF MS: m/z calcd for C12H19NO2: 296.1263;
(2S,6S)-2,6-Bis(N-phenylaminooxy)cyclohexanone (4a): [a]D =+115.4
(c=0.1 in CHCl3); 1H NMR (CDCl3): d=1.94 2.06 (m, 2H;
CH2CH2CH2), 2.08 2.14 (m, 4H; CH2CH2CH), 4.68 (q, J=6.0 Hz, 2H;
Chem. Eur. J. 2004, 10, 3673 3684
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3681

A. CÛrdova et al.
FULL PAPER
found: 296.1260 [M+Na]+; HPLC (hexanes/iPrOH 95:5): major isomer:
tR =41.1 min; minor isomer: tR =36.3 min.
clear solution was filtered through Celite. The filtrate was concentrated
under reduced pressure, and the crude product was purified by silica gel
column chromatography (EtOAc/pentane 1:2) to afford the correspond-
ing deprotected adduct.
(2R)-3-Methyl-2-(N-phenylaminooxy)butan-1-ol (6n): [a]D =+39.1 (c=
0.9 in CHCl3); 1H NMR (CDCl3): d=0.99 (d, J=6.6 Hz, 3H; CH3), 1.04
(d, J=6.6 Hz, 3H; CH3), 2.03 (m, 1H; CH(CH3)2), 2.88 (brs, 1H; OH),
3.72 (m, 1H; CHONHAr), 3.85 (m, 2H; CH2OH), 6.95 (m, 3H; ArH),
7.06 (s, 1H; ONHAr), 7.25 ppm (m, 2H; ArH); 13C NMR: d=18.7, 18.8,
28.8, 63.8, 88.7, 114.9, 122.4, 128.9, 148.1 ppm; MALDI-TOF MS: m/z
calcd for C11H18NO2 196.1337; found: 196.1339 [M]+; HPLC (hexanes/
iPrOH 95:5): major isomer: tR =15.1 min; minor isomer: tR =11.3 min.
À
Typical experimental procedure for CuSO4-mediated N O bond cleav-
age: A catalytic amount of CuSO4¥H2O (30 mol%) was added at 08C to
a vial containing the a-adduct (1 mmol) in MeOH (3 mL). The reaction
mixture was stirred at this temperature until completion as determined
by TLC analyses and then quenched by addition of aqueous NH4Cl. The
aqueous phase was extracted three times with EtOAc. The combined or-
ganic layers were dried with MgSO4, which was subsequently removed by
filtration. The solvent was removed under reduced pressure after purifi-
cation of the crude product mixture by silica gel column chromatography
(EtOAc/pentane 1:2) to afford the corresponding a-deprotected adduct.
(2S)-3-Methyl-2-(N-phenylaminooxy)butan-1-ol (ent-6n): This product
was obtained from (R)-proline catalysis. [a]D =À39.0 (c=0.7 in CHCl3);
HPLC (hexanes/iPrOH 95:5): major isomer: tR =11.3 min; minor isomer:
tR =15.1 min.
(2R)-Hexane-1,2-diol (7b): This product was obtained from (S)-proline
catalysis. [a]D =+22.2 (c=1.1 in EtOH); 1H NMR (CDCl3): d=1.29 (t,
J=7.2 Hz, 3H; CH3), 1.51 1.84 (m, 6H; CH2CH2CH2), 3.17 (brs, 2H;
OH), 3.80 (m, 1H; CH2OH), 4.06 ppm (m, 2H; CH2OH, CHOH); 13C
NMR: d=14.6, 23.3, 33.4, 67.4, 72.9 ppm.
(2R)-2-(N-Phenylaminooxy)pent-4-en-1-ol (6o): [a]D =+8.1 (c=0.8 in
CHCl3); 1H NMR (CDCl3): d=1.80 (m, 1H; OH), 2.51 2.67 (m, 2H;
CH2CH=CH2), 3.76 (dd, J=11.7, 6.0 Hz, 1H; CH2OH), 3.85 (dd, J=11.7,
2.7 Hz, 1H; CH2OH), 3.96 (dq, J=6.6, 2.7 Hz, 1H; CHONHAr); 4.98 (d,
J=10.2 Hz, 1H), 5.05 (d, J=17.4 Hz, 1H), 5.82 (m, 1H), 6.97 (m, 3H),
7.06 (s, 1H), 7.25 ppm (m, 2H); 13C NMR: d=29.2, 29.9, 65.1, 83.3,
114.8, 115.0, 122.4, 128.9, 137.8, 148.2 ppm; MALDI-TOF MS: m/z calcd
for C12H18NO2: 208.1337; found: 208.1339 [M]+; HPLC (hexanes/iPrOH
95:5): major isomer: tR =26.3 min; minor isomer: tR =19.8 min.
(2S)-Hexane-1,2-diol (ent-7b): This product was obtained from (R)-pro-
line catalysis. [a]D =À22.0 (c=0.9 in EtOH).[35]
(2R)-3-Methylbutane-1,2-diol (7n): This product was obtained from (S)-
proline catalysis. [a]D =À11.1 (c=0.6 in CHCl3); 1H NMR (CDCl3): d=
0.91 (d, J=6.5 Hz, 3H), 0.98 (d, J=6.5 Hz, 3H), 1.71 (m, 1H), 3.42 (m,
1H), 3.51 (dd, J=10.5, 8.0 Hz, 1H), 3.71 ppm (dd, J=10.5, 3.0 Hz, 1H);
13C NMR: d=18.2, 18.7, 30.9, 64.9 ppm.[27]
(2R)-3-Phenyl-2-(N-Phenylaminooxy)propan-1-ol (6p): [a]D =+42.1 (c=
1
0.9 in CHCl3); H NMR (CDCl3): d=2.84 (dd, J=13.8, 6.6 Hz, 1H), 3.04
(dd, J=13.8, 6.6 Hz, 1H), 3.71 (dd, J=12.3, 6.3 Hz, 1H), 3.85 (dd, J=
12.3, 3.0 Hz, 1H), 4.09 (m, 1H), 6.82 (d, J=8.4 Hz, 2H), 6.92 (t, J=
7.5 Hz, 1H), 7.14 7.31 ppm (m, 7H); 13C NMR: d=36.6, 64.3, 85.1, 114.5,
122.2, 126.3, 128.3, 128.8, 129.3, 137.6, 148.1 ppm; MALDI-TOF MS: m/z
calcd for C15H18NO2: 244.1337; found: 208.1340 [M]+; HPLC (hexanes/
iPrOH 95:5): major isomer: tR =31.7 min; minor isomer: tR =21.4 min.
(2S)-3-Methylbutane-1,2-diol (ent-7n): This product was obtained from
(R)-proline catalysis. [a]D =+11.0 (c=0.6 in CHCl3).
(2S)-3-Phenylpropane-1,2-diol (ent-7p): This product was obtained from
(R)-proline catalysis. [a]D =À18.6 (c=1.3 in CHCl3); 1H NMR (CDCl3):
d=1.85 (brs, 2H; OH), 2.78 (m, 2H; PhCH2CH), 3.54 (m, 1H; CH2OH),
3.70 (m, 1H; CH2OH), 3.95 (m, 1H; CHOH), 7.24 (m, 3H; ArH),
7.33 ppm (m, 2H; ArH); 13C NMR: d=40.0, 66.3, 73.3, 126.9, 128.9,
129.6, 137.9 ppm.
(2S)-3-Phenyl-2-(N-phenylaminooxy)propan-1-ol (ent-6p): This product
was obtained from (R)-proline catalysis. [a]D =À42.2 (c=0.9 in CHCl3);
HPLC (hexanes/iPrOH 95:5): major isomer: tR =21.4 min; minor isomer:
tR =31.7 min.
(1S)-1-Phenylethane-1,2-diol (ent-7q): This product was obtained from
(R)-proline catalysis. [a]D =À38.1 (c=1.2 in CHCl3); 1H NMR (CDCl3):
d=2.56 (s, 2H; OH), 3.67 (dd, J=8.4, 11.6 Hz, 1H; CH2OH), 3.77 (dd,
J=10.8 Hz, 1H; CH2OH), 4.83 (dd, J=3.6, 8.0 Hz, 1H; ArCHOH),
7.29 7.34 ppm (m, 5H; ArH); 13C NMR: d=68.1, 74.4, 126.0, 128.0,
128.6, 140.5 ppm; HPLC (hexanes/iPrOH 95:5, l=254 nm): major
isomer: tR =33.0 min; minor isomer: tR =30.2 min.
cis-(2R)-2-(N-Phenylaminooxy)dec-7-en-1-ol (6s): [a]D =+11.9 (c=1.03
in CHCl3); 1H NMR (CDCl3): d=0.96 (t, J=0.019 Hz, 3H), 1.23 1.57
(m, 5H), 1.63 1.73 (m, 1H), 2.01 2.08 (m, 4H), 3.75 3.81 (m, 1H), 3.84
3.89 (m, 1H), 3.97 4.03 (m, 1H), 5.27 5.41, (m, 2H), 7.02 (m, 3H),
7.29 ppm (m, 2H); 13C NMR: d=14.6, 20.7, 25.6, 27.1, 30.1, 30.0, 65.7,
84.2, 115.1, 122.9, 128.9, 129.3, 132.1 ppm; MALDI-TOF MS: m/z calcd
for C16H25NO2: 263.1885; found: 263.1887 [M]+; HPLC (hexanes/iPrOH
95:5): major isomer: tR =21.7 min; minor isomer: tR =14.4 min.
trans-(1S,2S)-Cyclohexane-1,2-diol (7a): This product was obtained from
(S)-proline catalysis. [a]D =À39.1 (c=0.2 in CHCl3); 1H NMR (CDCl3):
d=1.26 (m, 4H; CH2), 1.75 (m, 2H; CH2), 1.98 (m, 2H; CH2), 3.34 ppm
(m, 2H; CHOH); 13C NMR: d=24.5, 33.1, 76.1 ppm.[28]
cis-Cyclohexane-1,2-diol (7a): 1H NMR (CDCl3): d=1.26 (m, 2H; CH2),
1.76 (m, 4H; CH2), 1.91 (m, 2H; CH2), 3.34 ppm (m, 1H; CHOH); 13C
NMR: d=21.6, 30.1, 70.8 ppm.
(2R)-2-Phenyl-2-(N-phenylaminooxy)ethanol (6t): [a]D =À142.1 (c=0.9
in CHCl3); 1H NMR (CDCl3): d=2.66 (dd, J=4.4, 7.7 Hz; OH), 3.86
3.85 (m, 1H; CH2OH), 3.91 4.03 (m, 1H; CH2OH), 5.01 (dd, J=4.4,
7.7 Hz, 1H; CHONHAr), 6.95 (m, 4H; ArH, ONHAr), 7.25 ppm (m,
2H; ArH); 13C NMR: d=66.7, 86.8, 115.3, 122.8, 127.3, 128.9, 129.3,
138.0, 148.3 ppm; MALDI-TOF MS: m/z calcd for C14H15NO2: 229.2744;
found: 229.2747 [M]+; HPLC (hexanes/iPrOH 95:5): major isomer: tR =
33.7 min; minor isomer: tR =22.4 min.
(2R)-2-Hydroxyketone 8a: This product was obtained from (S)-proline
catalysis. [a]D =+24.1 (c=0.72 in CHCl3).[29]
Direct asymmetric synthesis of epoxides: Freshly distilled pyridine
(4 mL) and toluenesulfonyl chloride (7.36 g, 40 mmol) were added to a
solution of 7 (20 mmol) in dry CH2Cl2 (50 mL) at 08C under nitrogen at-
mosphere. The mixture was stirred for 12 h at 08C and was then acidified
with HCl (2n). The organic layer was washed with brine, dried over
MgSO4, and concentrated in vacuo to furnish the monotosylate. The
crude monotosylate was dissolved in methanol (50 mL) and was treated
with potassium carbonate (2.1 g, 15 mmol) at 48C. The reaction was
quenched after 1 h by addition of water and extracted with EtOAc. The
combined organic extracts were dried with MgSO4, and the solvent was
subsequently removed by evaporation under reduced pressure. The resi-
due was purified by silica gel column chromatography (pentane/EtOAc
mixtures) to afford the corresponding epoxides 9.
(S)-(2,3-Epoxypropyl)benzene (9q): [a]D =17.6 (c=1.9 in CHCl3); 1H
NMR (CDCl3): d=2.55 (dd, J=4.8, 2.8 Hz, 1H), 2.79 (m, 1H), 2.81 (dd,
1H), 2.92 (dd, 1H), 3.19 (m, 1H), 7.27 (m, 3H), 7.31 ppm (m, 2H); 13C
NMR: 39.0, 47.1, 52.7, 126.9, 128.7, 129.2, 138.2 ppm.
(S)-Phenylethylene oxide (9t): [a]D =23.9 (c=0.8 in CHCl3); 1H NMR
(CDCl3): d=3.18 (dd, J=4.8, 2.8 Hz, 1H), 3.55 (dd, J=5.4, 4.4 Hz, 1H),
(2S)-2-Phenyl-2-(N-phenylaminooxy)ethanol (ent-6t): This product was
obtained from (R)-proline catalysis. [a]D =+141.9 (c=0.8 in CHCl3);
HPLC (hexanes/iPrOH 95:5): major isomer: tR =22.4 min; minor isomer:
tR =33.7 min.
(2R)-2-(N-Phenylaminooxy)-(1R)cyclohexanol (6a): dr=2:1 (anti:syn);
[a]D =+93.7 (c=0.4 in CHCl3); 1H NMR (CDCl3): d=1.21 1.44 (m,
4H), 1.59 (m, 2H), 1.66 (m, 4H), 1.88 (m, 2H), 1.93 (m, 1H), 2.14 (m,
1H), 3.65 (m, 1H; syn isomer), 3.92 (m, 1H; anti isomer), 4.11 (m, 1H;
anti isomer); 6.94 (m, 4.5H), 7.25 (m, 3H), 7.28 ppm (brs, 1.5H); 13C
NMR: d=21.3, 22.8, 24.1, 24.4, 26.4, 29.5, 30.8, 69.2, 74.5, 82.9, 86.5,
114.8, 115.3, 122.4, 122.8, 129.2, 148.6, 148.7 ppm; MALDI-TOF MS: m/z
calcd for C12H17NO2: 230.116; found: 230.117 [M+H]+; HPLC (hexanes/
iPrOH 90:10): major isomer: tR =88.09 min; minor isomer: tR =69.32 min.
À
Typical experimental procedure for N O bond cleavage by catalytic hy-
drogenation with Adams× catalyst: Methanol (3 mL) and Adams× catalyst
(10 mol%) were added to a 20 mL hydrogenation vial equipped with a
magnetic stirrer bar and charged with the a adduct (0.5 mmol). Next, the
reaction mixture was flushed with H2 (90 MPa) for 1 h and the resulting
3682
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 3673 3684

Asymmetric a-Aminooxylations
3673 3684
4.25 ppm (dd, J=4.0, 2.4 Hz 1H); 13C NMR: d=51.8, 53.0, 126.1, 128.8,
129.1, 138.2 ppm.
c) J. Grˆger, J. Wilken, Angew. Chem. 2001, 113, 515; Angew. Chem.
Int. Ed. 2001, 40, 529; d) E. R. Jarvo, S. J. Miller, Tetrahedron 2002,
58, 2481; e) R. O. Duthaler, Angew. Chem. 2003, 115, 1005; Angew.
Chem. Int. Ed. 2003, 42, 975.
Asymmetric synthesis of (S)-2-amino-1-phenylethanol (10t): The enantio-
merically pure epoxide 9t originating from (R)-proline-catalyzed a-oxi-
dation of aldehyde 1t (1 mmol) was regioselectively ring-opened accord-
ing to reference [32]. The crude azido alcohol product was dissolved in
MeOH (10 mL), and PtO2 (24 mg, 0.10 mmol) was added. The flask was
then flushed with hydrogen at 1 bar, and the reaction mixture was stirred
for 2 h at room temperature. The mixture was filtered through Celite,
and the solvent was removed under reduced pressure. The crude product
was purified by silica gel column chromatography (pentane/EtOAc 1:2)
to afford compound 10t as a white solid (127 mg, 91%). All spectroscop-
ic data were identical to those of the commercially available compound.
1H NMR (CDCl3): d=2.14 (brs, 2H; NH2), 2.82 (dd, J=12.6, 8.0 Hz,
2H; CH2NH2), 3.01 (dd, J=12.8, 4.0 Hz, 1H; CH2NH2), 4.64 (dd, J=5.6,
4.0 Hz, 1H; CHOH), 7.33 ppm (m, 5H; ArH); 13C NMR: d=49.74.5,
126.2, 127.9, 128.7, 139.2 ppm.
[7]a) Z. G. Hajos, D. R. Parrish, Asymmetric Synthesis of Optically
Active Polycyclic Organic Compounds. German Patent.
DE 2102623, July 29, 1971; b) Z. G. Hajos, D. R. Parrish, J. Org.
Chem. 1974, 39, 1615; c) U. Eder, G. Sauer, R. Wiechert, Optically
Active 1,5-Indanone and 1,6-Naphthalenedionene. German Patent
DE 2014757, October 7, 1971; d) U. Eder, G. Sauer, R. Wiechert,
Angew. Chem. 1971, 83, 492; Angew. Chem. Int. Ed. 1971, 10, 496;
e) C. Agami, Bull. Soc. Chim. Fr. 1988, 499.
[8]For example, the total synthesis of taxol: S. J. Danishefsky, J. Am.
Chem. Soc. 1996, 118, 2843.
[9]Aldol reactions, see: a) B. List, R. A. Lerner, C. F. Barbas, III, J.
Am. Chem. Soc. 2000, 122, 2395; b) W. Notz, B. List, J. Am. Chem.
Soc. 2000, 122, 7386; c) K. Saktihvel, W. Notz, T. Bui, C. F. Barbas,
III, J. Am. Chem. Soc. 2001, 123, 5260; d) A. CÛrdova, W. Notz,
C. F. Barbas, III, J. Org. Chem. 2002, 67, 301; e) B. List, P. Pojarliev,
C. Castello, Org. Lett. 2001, 3, 573; f) A. CÛrdova, W. Notz, C. F.
Barbas, III, Chem. Commun. 2002, 3034; g) A. B˘gevig, K. Juhl, N.
Kumaragurubaran, K. A. J˘rgensen, Chem. Commun. 2002, 620;
h) A. B. Northrup, D. W. C. MacMillan, J. Am. Chem. Soc. 2002,
124, 6798; i) N. S. Chowdari, D. B. Ramachary, A. CÛrdova, C. F.
Barbas, III, Tetrahedron Lett. 2002, 43, 9591; j) C. Pidathala, L.
Hoang, N. Vignola, B. List Angew. Chem. 2003, 115, 2891; Angew.
Chem. Int. Ed. 2003, 42, 2785; k) Z. Tang, F. Jiang, L.-T. Yu, X. Cui,
L.-Z. Gong, A.-Q. Mi, Y.-Z. Jiang, Y. D. Wu, J. Am. Chem. Soc.
2003; 125, 5262.
[10]Mannich reactions see: a) B. List, J. Am. Chem. Soc. 2000, 122,
9336; b) B. List, P. Porjaliev, W. T. Biller, H. J. Martin, J. Am. Chem.
Soc. 2002, 124, 827; c) W. Notz, K. Sakthivel, T. Bui, G. Zhong, C. F.
Barbas, III, Tetrahedron Lett. 2001, 42, 199; d) A. CÛrdova, W.
Notz, G. Zhong, J. M. Betancort, C. F. Barbas, III, J. Am. Chem.
Soc. 2002, 124, 1844; e) A. CÛrdova, Synlett 2003, 1651; f) A. CÛrdo-
va, Chem. Eur. J. 2004, 10, 1957; g) A. CÛrdova, S.-I. Watanabe, F.
Tanaka, W. Notz, C. F. Barbas, III, J. Am. Chem. Soc. 2002, 124,
1866; h) A. CÛrdova, C. F. Barbas, III, Tetrahedron Lett. 2002, 43,
7749; i) A. CÛrdova, C. F. Barbas, III, Tetrahedron Lett. 2003, 44,
1923; j) S.-I. Watanabe, A. CÛrdova, F. Tanaka, C. F. Barbas, III,
Org. Lett. 2002, 4, 4519; k) Y. Hayashi, W. Tsuboi, I. Ashimine, T.
Urushima, M. Shoji, K. Sakai, Angew. Chem. 2003, 115, 3805;
Angew. Chem. Int. Ed. 2003, 42, 3677; l) A. CÛrdova, Acc. Chem.
Res. 2004, 37, 102.
Asymmetric synthesis of (S)-2-(2-propylamino)-1-phenylethanol (11t):
The enantiomerically pure epoxide 9t originating from (R)-proline-cata-
lyzed a-oxidation of aldehyde 1t (1 mmol) was regioselectively ring-
opened according to reference [32]. The crude azido alcohol product was
dissolved in MeOH (10 mL), and PtO2 (12 mg, 0.05 mmol), molecular
sieves (3 ä, 0.45 g), and acetone (110 mL, 1.1 mmol) were added. The
flask was then flushed with hydrogen at 1 bar, and the reaction mixture
was stirred for 5 h at room temperature. The mixture was filtered through
Celite, and the solvent was removed under reduced pressure. The crude
product was purified by silica gel column chromatography (pentane/
EtOAc 1:2) to afford compound 11t as a white solid (237 mg, 92%). All
spectroscopic data were identical to those of the previously described
compound. 1H NMR (CDCl3): d=0.96 (d, J=8.9 Hz, 6H; CH3), 2.49
2.65 (m, 2H), 3.40 3.53 (m, 1H), 4.58 4.65 (m, 1H; CHOH), 7.33 ppm
(m, 5H; ArH).[36]
Computational details: All geometries and energies presented in this
study were computed by use of the B3LYP[37] density functional theory
method as implemented in the Gaussian 98 program package.[38] Geome-
try optimizations were performed with the double zeta plus polarization
basis set 6 31G(d,p). From these geometries, single-point calculations
with the larger 6 311+G(2d,2p) basis set were performed in order to
obtain more accurate energies. Hessians for evaluation of zero-point vi-
brational effects were calculated at the B3LYP/6 31G(d,p) level of
theory.
[11] a-Aminations see: a) A. B˘gevig, K. Juhl, N. Kumaragurubaran, W.
Zhuang, K. A. J˘rgensen, Angew. Chem. 2002, 114, 1868; Angew.
Chem. Int. Ed. 2002, 41, 1790; b) B. List, J. Am. Chem. Soc. 2002,
124, 5656; c) N. Kumaragurubaran, K. Juhl, W. Zhuang, A. B˘gevig,
K. A. J˘rgensen, J. Am. Chem. Soc. 2002, 124, 6254.
Acknowledgment
Support by Prof. J.-E. B‰ckvall and Stockholm University is gratefully ac-
knowledged. We thank Prof. H. Adolfsson for valuable discussions and
the Swedish National Research council, the Lars Hierta Foundation, and
the Wenner Gren Foundation for financial support.
[12]Michael reactions see: a) B. List, P. Pojarliev, H. B. Martin, Org.
Lett. 2001, 3, 2423; b) M. Yamaguchi, T. Shiraishi, M. Hirama, J.
Org. Chem. 1996, 61, 3520; c) M. Yamaguchi, Y. Igarashi, R. S.
Reddy, T. Shiraishi, M. Hirama, Tetrahedron 1997, 53, 11223; c) M.
Yamaguchi, Y. Igarashi, T. Shiraishi, M. Hirama, Tetrahedron Lett.
1994, 35, 8233; d) S. Hanessian, V. Pham, Org. Lett. 2000, 2, 2975;
e) J. M. Betancort, K. Sakthivel, R. Thayumanavan, C. F. Barbas,
III, Tetrahedron Lett. 2001, 42, 4441; f) J. M. Betancort, C. F.
Barbas, III, C. F . Org. Lett. 2001, 3, 3737; g) D. J. Hortsmann, D. J.
Guerin, S. J. Miller, Angew. Chem. 2000, 112, 3781; Angew. Chem.
Int. Ed. 2000, 39, 3635; h) A. Alexakis, O. Andrey, Org. Lett. 2002,
4, 3611; i) D. J. Guerin, S. J. Miller, J. Am. Chem. Soc. 2002, 124,
2134; j) N. Halland, P. S. Aburel, K. A. J˘rgensen, Angew. Chem.
2003, 115, 685; Angew. Chem. Int. Ed. 2003, 42, 661; k) N. Halland,
R. G. Hazell, K. A. J˘rgensen, J. Org. Chem. 2002, 67, 8331; l) O.
Andrey, A. Alexakis, G. Bernardinelli, Org. Lett. 2003, 5, 2559;
m) D. Enders, A. Seki, Synlett 2002, 26.
[1]a) Comprehensive Asymmetric Catalysis (Eds.: E. N. Jacobsen, A.
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Asymmetric Catalysis in Asymmetric in Organic Synthesis, Wiley,
New York, 1994; c) Catalytic Asymmetric Synthesis (Ed.: I. Ojima),
2nd ed, Wiley-VCH, New York, 2000.
[2]a) F. A. Davis, B. C. Chen, Methods of Organic Chemistry (Houben
Weyl) Vol. E21 (Eds.: G. Helmchen, R. W. Hoffmann, J. Mulzer, E.
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Received: February 10, 2004
Published online: June 8, 2004
3684
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 3673 3684