Variable C2-symmetric analogues of N-hydroxyphthalimide as enantioselective catalysts for aerobic oxidation: Kinetic resolution of oxazolidines

Article abstract of DOI:10.1002/anie.200603780

(Chemical Equation Presented) Fast and selective: The aerobic oxidative ring opening of oxazolidine 1 in the presence of a catalytic amount of the chiral N-hydroxyphthalimide analogue 2 was accompanied by efficient kinetic resolution of the oxazolidine. T

Full text of DOI:10.1002/anie.200603780

Communications
DOI: 10.1002/anie.200603780
Asymmetric Catalysis
Variable C2-Symmetric Analogues of N-Hydroxyphthalimide as
Enantioselective Catalysts for Aerobic Oxidation: Kinetic Resolution
of Oxazolidines**
Malek Nechab, Dhondi Naveen Kumar, Christian Philouze, Cathy Einhorn, and
Jacques Einhorn*
In memory ofAndrØ Rassat
During the past decade, aerobic oxidation catalyzed by
N-hydroxyphthalimide (NHPI) or its analogues has emerged
as a powerful tool in organic synthetic methodology.This
technique allows the selective and mild oxidation or, more
generally, the functionalization of a broad variety of organic
compounds, including alkanes, benzylic hydrocarbons,
alkenes, alkynes, alcohols, ethers, amides, and acetals,[1,2]
under environmentally benign conditions.Catalysis proceeds
via an intermediate phthalimide N-oxyl radical (PINO): a
reactive nitroxide-type radical able to abstract a hydrogen
atom from the substrate.The resulting carbon-centered
radical then combines with molecular oxygen.[3] In this
context, we reported previously the synthesis of axially
chiral analogues of NHPI.These analogues exhibited
modest enantioselectivities in some representative asymmet-
ric oxidation reactions, such as the desymmetrization of
2-substituted indanes and the kinetic resolution of racemic
acetals.[4] Herein we report a straightforward approach to the
synthesis of variable C2-symmetric analogues of NHPI from
diphenol 1, which can be obtained in high diastereomeric
purity by thermal isomerization in the solid state.[5] We
reported previously an efficient resolution of (ꢀ )-1 via the
corresponding N(a)-Boc-tryptophan diesters; each enantio-
mer of 1 is now readily available with > 99% ee.Additionally,
the absolute configuration of the two enantiomers has been
established.[6]
to give cleanly the N-hydroxyimide 3 as a result of nucleo-
philic attack of hydroxylamine solely at the imide moiety of 2
without affecting the phenolic Boc groups.Allylic or benzylic
protection of the N-hydroxyimide functionality was then
followed by acidic removal of the phenolic Boc groups.The
precatalysts 4a and 4b were thus obtained from 1 in 90 and
88% overall yield, respectively (Scheme 1).The whole
Scheme 1. a) Boc2O (3 equiv), DMAP (10 mol%), CH3CN, RT; b) aq
NH2OH (1 equiv), CH3CN, RT; c) allyl bromide, K2CO3, acetone, RT;
d) benzyl bromide, K2CO3, DMSO, RT; e) TFA/CH2Cl2 (1:1), RT.
Bn=benzyl, Boc=tert-butoxycarbonyl, DMAP=4-dimethylaminopyri-
dine, DMSO=dimethyl sulfoxide, TFA=trifluoroacetic acid.
sequence was carried out at room temperature, thus avoiding
thermal atropisomerization of configurationally fragile com-
pounds.[5,6] Compounds (aS,aS)-4a and (aS,aS)-4b were
obtained from (aS,aS)-1 (> 99% ee) with no loss of enantio-
meric purity.
The principle of the present approach is the selective
transformation of the imide function of 1 into an N-
hydroxyimide,[7] and the use of the phenolic moieties as
handles to introduce variable substituents.First, 1 was
converted into the tris-Boc-functionalized derivative 2 with
di-tert-butyldicarbonate (Boc2O) in the presence of DMAP.
Gratifyingly, 2 reacted with aqueous hydroxylamine (1 equiv)
Some transformations of 4a and 4b into functionally and
structurally diverse C2-symmetric NHPI analogues are
depicted in Scheme 2.Thus, 4a and 4b react readily with
acid chlorides to give catalysts of type 5 after deprotection of
the N-hydroxyimide.Similarly, chloroformates, alkyl halides,
chlorosilanes, and isocyanates react as electrophiles to give
catalysts of type 6, 7, 8, and 9, respectively.As mentioned
previously, atropisomerization can be avoided by conducting
the reactions at or below room temperature.In this way a
broad variety of enantiopure catalysts are readily available
from enantiopure 4a or 4b.Some representative examples
are given in Table 1.Thus, 4b reacted quantitatively with
benzoyl chloride (2 equiv) in the presence of Et3N.Removal
of the benzyl protecting group under standard conditions then
gave diester 5a (Table 1, entry 1).Compound 4a was treated
[*] Dr. M. Nechab, Dr. D. N. Kumar, Dr. C. Philouze, Dr. C. Einhorn,
Dr. J. Einhorn
DØpartement de Chimie MolØculaire (SERCO)
UMR-5250, ICMG FR-2607, CNRS, UniversitØ Joseph Fourier
BP-53, 38041 Grenoble Cedex 9 (France)
Fax: (+33)4-7651-4836
E-mail: jacques.einhorn@ujf-grenoble.fr
[**] Financial support from the UniversitØ Joseph Fourier and the CNRS
is gratefully acknowledged. M.N. and D.N.K. thank the DCM for
financial support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Chemie
The aerobic oxidation of acetals to esters catalyzed by
NHPI under mild conditions was reported recently.[9] In
particular, 1,3-dioxolanes are oxidized efficiently to ethyl-
eneglycol monoesters by ring opening.We discovered that an
analogous oxidative ring opening occurs with N-acyl oxazo-
lidines[10] in the presence of NHPI-type catalysts: The aerobic
oxidation of 10a[10b] as an 0.01m solution in CH3CN at 358C in
the presence of catalytic amounts of N-hydroxy-3,4,5,6-
tetraphenylphthalimide (NHTPPI)[11] and CuCl gave 11a in
100% yield (Scheme 3).
We found that chiral analogues of NHPI are also able to
catalyze the oxidation of 10a to 11a.Interestingly, the partial
oxidation of racemic 10a with enantiopure catalysts occurs
with kinetic resolution of the remaining 10a.The efficiency of
the kinetic resolution is highly dependent on the catalyst used
(Table 2).When the reaction depicted in Scheme 3 was
Scheme 3. Oxidative ring opening of oxazolidine 10a catalyzed by
NHTPPI.
Scheme 2. Synthesis of functionally and structurally diverse C2-sym-
metric NHPI analogues.
performed with catalyst 5a, 52% conversion was observed
after 24 h; the remaining 10a had an ee value of 23%: These
values correspond to a stereoselectivity factor s[12] of 1.9
(Table 2, entry 1).No significant improvements were
observed with catalysts of type 6, 7, or 8 (Table 2, entries 2–
7).The results obtained with carbamate-type catalysts were
more remarkable: The use of catalyst 9a led to 53%
conversion and 50% ee for the remaining 10a, which
with methyl or phenyl chloroformate in the presence of Et3N
and a catalytic amount of DMAP.Allyl deprotection [8] of the
products then gave dicarbonates 6a and 6b (Table 1, entries 2
and 3).Similarly, diethers 7a and 7b (Table 1, entries 4 and 5),
bis(silyl ether)s 8a and 8b (entries 6 and 7), and dicarbamates
9a–9e (entries 8–12), were prepared readily.
Table 1: C2-symmetric NHPI analogues prepared according to Scheme 2.
Table 2: Oxidative kinetic resolution of oxazolidine 10a catalyzed by
Entry
4[a]
Electrophile
Catalyst[b]
Yield [%][c]
enantiomerically pure NHPI analogues.[a]
1
2
3
4
4b
4a
4a
4b
PhCOCl
MeOCOCl
PhOCOCl
5a R=Ph
6a R=Me
6b R=Ph
7a R=nPr[d]
80
78
78
46
Entry
Catalyst
Conversion [%][b]
ee [%][c]
s
1
2
3
4
5
6
7
8
9
5a
6a
6b
7a
7b
8a
8b
9a
9b
52
38
37
43.5
75
47
64.5
53
25
52
50
23
22
20
4
1.9
2.6
2.4
1.15
1.5
1.9
1.8
4.1
6
5.8
9
6.5
–
5
6
7
8
9
4b
4b
4b
4b
4b
4a
80
7b R=
TBDMSCl
TIPSCl
PhNCO
1-naphthyl-NCO
BnNCO
8a SiR3 =TBDMS
8b SiR3 =TIPS
9a R=Ph
9b R=1-naphthyl
9c R=Bn
97
50
84
28
20
30
50
22
58
65
91
99
20[e]
28[e]
31 (72)[e]
68
10
10[d]
11[d]
12
13
14
15
9b
9c
9d
9d R=
9e R=
11
12
4b
96
84
4a[f]
70
80
27
75
9d[d]
9e[d]
(ꢁ)-12[f]
4
1.5
[a] Unless otherwise indicated, (aS,aS)-4a and (aS,aS)-4b were used.
[b] Deprotection method used for catalysts prepared from 4a: sodium 2-
ethylhexanoate (1.5 equiv), [Pd(PPh3)4] (2 mol%), AcOEt/CH2Cl2 (1:2),
RT; deprotection method used for catalysts prepared from 4b: H2
(atmospheric pressure), 10%Pd/C (0.25 g per mmol of 4b), AcOEt,
RT. [c] Unoptimized overall yield of the isolated pure catalyst. [d] Hydro-
genation of the double bonds occurs during hydrogenolysis. [e] The yield
based on recovered 4b is given in brackets. [f] Compound (aR,aR)-4a
was used. TBDMS=tert-butyldimethylsilyl, TIPS=triisopropylsilyl.
[a] Reaction conditions, unless otherwise indicated: 10a (0.01m),
catalyst (4 mol%), CuCl (5 mol%), CH3CN, 358C, 24 h. [b] Determined
by GC. [c] Determined by HPLC with a Chiralpak AS column. Unless
otherwise indicated, the major remaining enantiomer of 10a was the first
enantiomer eluted. [d] A 0.1m solution of 10a in CH3CN was used.
[e] The major remaining enantiomer was the second enantiomer eluted.
[f] The reaction was performed with 6 mol%of the catalyst.
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Table 3: Oxidative kinetic resolution of various N-acyl oxazolidines 10
catalyzed by 9d.[a]
corresponds to s = 4.1 (Table 2, entry 8). With catalyst 9b only
25% conversion was observed, but with a stereoselectivity
factor of 6.The conversion could be increased to 52% by
using a 0.1m solution of 10a while maintaining a similar
s factor (Table 2, entries 9 and 10).A stereoselectivity factor
of 9 was found for catalyst 9c, but the conversion was limited
to 50% (Table 2, entry 11).Catalyst 9d combined high
conversion with good selectivity: When the initial concen-
tration of 10a was 0.01m, 70% conversion occurred to leave
10a with 91% ee (s = 6.5). A ten-fold increase in the substrate
concentration resulted in 80% conversion and 99% ee
(Table 2, entries 12 and 13).In contrast, much lower con-
version was observed with the diastereomeric catalyst 9e,
along with a lower s factor (Table 2, entry 14).The use of the
Entry Substrate
R
t [h] Conv. [%][b] ee [%][c] s[d]
1
2
3
4
5
6
10a
10b
10c
10d
10e
10 f
10 f
10 f
Ph
Me
tBu
1-naphthyl
24
16
4
80
50
50
75
50
99
25[e]
26
50
45
67
99
70
6.5
2.1[f]
2.2
2.1
4
8.7
–
9.1
2
p-NO2C6H4 24
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
0.8 52
1.2 75
2
7
8[g]
52.5
9
10
10g
10h
10i
10j
10k
10l
10l
10m
10n
Me
iPr
tBu
o-FC6H4
o-ClC6H4
o-BrC6H4
o-BrC6H4
p-BrC6H4
o-IC6H4
1.5 43
1.2 59
1.5 76
36
80
76
84
89
60
97
90[h]
60
4
8.2
4.9
11
12
13
14
15
16
17
1
2
51.6
50.5
21
41
24
–
7.3
>50
3.2 40.5
22
58
0.6 67
2.3 39
[a] Reaction conditions, unless otherwise indicated: 10 (0.1m), 9d
(4 mol%), CuCl (5 mol%), CH3CN, 358C. [b] The conversion was
determined by NMR spectroscopy with triphenylmethane as a standard.
[c] Unless otherwise indicated, the ee value was determined by HPLC
with a Chiralpak AS column, and the major remaining enantiomer was
the first enantiomer eluted. [d] For s>20, the indicated values are an
average of multiple experiments, whereas the corresponding values for
conversion and ee are for a specific case. [e] The major remaining
enantiomer was the second enantiomer eluted. [f] The reaction was
performed at 208C. [g] The reaction was performed with 1 mol%of 9d.
[h] The ee value was determined by HPLC with a Chiracel OD-H column.
first-generation catalyst (ꢁ)-12[4] led to 75% conversion and
28% ee for the remaining 10a, which corresponds to an
s factor of only 1.5 (Table 2, entry 15). Optically active 10a
has not been described previously, nor has the absolute
configuration of the individual enantiomers been reported.
Accordingly, the major enantiomer remaining after kinetic
resolution is indicated in Table 2 by reference to the elution
order of the enantiomers on a Chiralpak AS HPLC column.
When catalysts with stereogenic axes of configuration aS,aS
were used (Table 2, entries 1–13), the major remaining
enantiomer of 10a was always eluted faster than the minor
enantiomer.In the case of catalyst 9e, which has the absolute
configuration aR,aR, the major remaining enantiomer was
eluted more slowly than the minor enantiomer.The absolute
configuration of (ꢁ)-12 is still unknown.
was reduced to 1 mol%, 52.5% conversion was observed
after 2 h, and the remaining 10 f had an ee value of 70%, with
no significant change in the s factor (Table 3, entries 6–8).
N-p-Methoxybenzoyloxazolidines 10g, 10h, and 10i, with
methyl, isopropyl, and tert-butyl substituents at the 2-position,
respectively, were all oxidized at fast rates, and with
stereoselectivity factors ranging from 4 to 8.2 (Table 3,
entries 9–11).The oxidation rate of the o-fluorophenyl-
oxazolidine 10j was comparable to that of 10 f, but the
associated s factor was much higher: After 1 h, the conversion
was 51.6%, and the remaining 10j had an ee value of 84%,
which corresponds to an s factor close to 21 (Table 3,
entry 12).An s factor of about 40 was found for the oxidation
of its chlorinated analogue 10k, with only a slight decrease in
the reaction rate (Table 3, entry 13).The stereoselectivity
factor associated with the o-bromophenyl analogue 10l was
close to 24.The remaining oxazolidine 10l was obtained with
97% ee at 58% conversion (Table 3, entries 14 and 15).In
contrast, the s factor of the p-bromophenyl analogue 10m was
only 7.3 (Table 3, entry 16). Finally, after 39% conversion of
the o-iodophenyloxazolidine 10n in the presence of 9d, the
remaining oxazolidine had an ee value of 60%, which
corresponds to a stereoselectivity factor larger than 50
We next examined the oxidative kinetic resolution of a
series of N-acyl oxazolidines with catalyst 9d (Table 3).The
associated stereoselectivity factors of N-acetyl, N-pivaloyl, N-
1-naphthoyl, and N-p-nitrobenzoyl analogues 10b, 10c, 10d,
and 10e were significantly lower than that of the N-benzoyl
derivative 10a (Table 3, entries 1–5).The p-methoxybenzoyl
derivative 10 f was oxidized rapidly and selectively: After
50 min the conversion was 52%, and the remaining 10 f had
an ee value of 67%, with a corresponding stereoselectivity
factor of about 9.After 12. h, 75% conversion had occurred,
and 99% ee was observed for 10 f.When the amount of 9d
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(Table 3, entry 17).[13] To our knowledge, this is the highest
reported s factor for a radical reaction.[14] The absolute
configuration was not known for any of the oxazolidines in
the series 10b–n.Enantiopure 10l was obtained by recrystal-
lization of a sample of the resolved compound with 97% ee.
The oxazolidine stereogenic center was assigned the R confi-
guration unambiguously by anomalous X-ray diffraction,
which was made possible by the bromine atom.[15] Thus, the
S enantiomer of 10l reacted faster than the R enantiomer
when catalyst 9d was used.Further studies are necessary to
assign the absolute configuration of other resolved oxazoli-
dines, but it is reasonable to anticipate similar behavior, at
least for oxazolidines 10 f, 10j, 10k, 10m, and 10n.
In summary, we have reported the synthesis of readily
variable, C2-symmetric analogues of NHPI.These analogues
exhibit catalytic activity in the oxidative ring opening of
various N-acyl oxazolidines.The kinetic resolution of racemic
oxazolidines is possible with enantiopure catalysts, with
selectivity factors that are highly dependent on the substitu-
tion pattern of the catalyst.Fast reaction rates and selectivity
factors larger than 20 were observed in some cases with the
most efficient catalyst examined.Such catalysts could be of
value for the synthesis of highly enantiomerically enriched
oxazolidines.[16] The resolved compounds 10k, 10l, and 10n
could be useful as synthetic intermediates, for example, in
asymmetric cross-coupling reactions.However, the synthetic
potential of enantiopure oxazolidines remains to be fully
established.Oxazolidines also exhibit interesting biological
properties: Several racemic oxazolidines have been reported
to be insect repellents.It would be interesting to test the
activities of individual enantiomers.Preliminary studies
indicate that other types of substrates, such as silyl ethers of
racemic secondary alcohols, are also oxidized by our new
catalysts with kinetic resolution.The examination of these
and further synthetic applications, as well as further improve-
ment of the catalysts and mechanistic investigations, is
currently under way.
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[10] N-Acyl oxazolidines of type 10 are readily available by the
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J. Heterocycl. Chem. 1968, 5, 587 – 590; b) S.G.Konꢀkova, A.E.
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[11] M.Nechab, C.Einhorn, J.Einhorn,
1500 – 1501.
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[12] The stereoselectivity factor s was determined by using the
equation: s = krel(fast/slow) = ln[(1ꢁC)(1ꢁee)]/ln[(1ꢁC)(1+ee)], in
which C is conversion; see: H.B.Kagan, J.C.Fiaud in Topics in
Stereochemistry, Vol. 18 (Ed.: E. L. Eliel), Wiley, New York,
1988, pp.249 – 330.
[13] For the efficient kinetic resolution of secondary alcohols by
palladium-catalyzed aerobic oxidation, see: a) R.J. Nielsen,
J.M.Keith, B.M.Stoltz, W.A.Goddard III,
J. Am. Chem. Soc.
2004, 126, 7967 – 7974; b) JA. .Mueller, A.Cowell, BD. .
Chandler, M.S.Sigman, J. Am. Chem. Soc. 2005, 127, 14817 –
14824, and references therein.
[14] For a review on enantioselective radical processes, see: M.P.
Sibi, S.Manyem, J.Zimmerman, Chem. Rev. 2003, 103, 3263 –
3295.
[15] Crystallographic data for (R)-10l (C17H16BrNO3): crystal dimen-
sions: 0.40 ” 0.33 ” 0.24 mm3, monoclinic, space group P21, a =
7.440(2), b = 7.070(2), c = 15.429(5) Š, b = 102.48(2)8, V=
792.5(4) Š3, Z = 2, 1calcd = 1.518 Mgmꢁ3, 2qmax = 608, MoKa radi-
ation (l = 0.71073 Š), phi and omega scan modes, T= 150 K,
Received: September 14, 2006
Revised: November 21, 2006
Published online: March 20, 2007
27269 reflections collected, 5525 independent reflections (Rint
=
Keywords: asymmetric catalysis · kinetic resolution · oxidation ·
oxygen · radical reactions
0.04), 4918 reflections used with I > 2.0s.The data were
corrected for Lorentz and polarization effects, and for absorp-
tion by using SADABS.The structure was solved by direct
methods by using SIR92 and refined against j F j by using a
least-squares technique implemented from the TeXsan program
(198 parameters).The hydrogen atoms were set geometrically
and were recalculated before the last refinement cycle. R =
0.0393, wR = 0.0447, Flack parameter: 0.0708(9). CCDC-
627511 contains the supplementary crystallographic data for
this paper.These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
.
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[16] For experimental details of the synthesis of the catalysts and
substrates, for experimental details of the asymmetric oxidation
reactions, and for an ORTEP drawing of (R)-10l, see the
Supporting Information.
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