Organocatalytic asymmetric α-aminoxylation/aza-michael reactions for the synthesis of functionalized tetrahydro-1,2-oxazines

Article abstract of DOI:10.1002/anie.200803731

(Chemical Equation Presented) Catalyst for THOught: The title reaction using acyclic nitroalkenals for the asymmetric installation of both C-O and C-N bonds led to functionalized tetrahydro-1,2-oxazines (THOs) having up to three stereogenic centers; the products were isolated in up to 90 % yield with excellent enantioselectivity and complete diastereoselectivity (see scheme). DFT calculations reveal an unprecedented transition state containing a molecule of water, which assists in the C-N bond-forming step by participating in two hydrogen bonds.

Full text of DOI:10.1002/anie.200803731

Angewandte
Chemie
DOI: 10.1002/anie.200803731
Asymmetric Domino Reactions
Organocatalytic Asymmetric a-Aminoxylation/Aza-Michael Reactions
for the Synthesis of Functionalized Tetrahydro-1,2-oxazines**
Min Lu, Di Zhu, Yunpeng Lu, Yuxuan Hou, Bin Tan, and Guofu Zhong*
Dedicated to Professor Richard A. Lerner on the occasion of his 70th birthday
Enantiopure 1,2-oxazines are prevalent in complex natural
products[1] and are versatile building blocks for asymmetric
synthesis. They are potential scaffolds which can be elabo-
rated into medicinal targets.[2] Although a number of reports
document methodologies devised for the synthesis of 1,2-
oxazine derivatives,[3] only two general routes for tetrahydro-
1,2-oxazines (THOs) have been used including the addition of
nitrones to activated cyclopropanes, which was developed by
Sibi et al.,[4a] and the sequential nitroso aldol/Michael addi-
tion of cyclic enones reported by Yamamoto et al.[4b,c] How-
ever, the substrate scope for these two examples are limited,
and the development of a practical, asymmetric synthetic
procedure to access enantiopure functionalized THOs from
acyclic starting materials is highly desirable.
Recently, the field of asymmetric catalysis has included
organocatalysis involving chiral secondary amine catalysts[5]
which is amenable to domino processes.[6] a-Aminoxylation[7]
directed tandem reactions[3g,h,8] were first developed by our
group,[8a,b] demonstrating the advantages of a rapid, catalytic,
and atom-economical process that yielded enantiomerically
pure products. This approach therefore seemed ideal for the
À
asymmetric introduction of an O N moiety. Our ongoing
interest in organocatalytic domino reactions,[9] combined with
the challenge of utilizing the amine component, generated
after the first aminoxylation step, in a subsequent step
prompted us to investigate the domino a-aminoxylation/
aza-Michael reaction for the synthesis of enantiopure func-
tionalized THOs.
Scheme 1. Proposed synthesis of chiral THO 1. a) Enantioselective
À
À
organocatalytic THO synthesis by a C O/C N sequence. b) Enamine-
catalyzed a-aminoxylation versus Michael addition. c) Aza-Michael
=
addition versus nucleophilic attack on the C O group and subsequent
asymmetric protonation. EWG=electron-withdrawing group.
The structure of THO 1 can be assembled by using two
À
À
reactions to form both the C O and C N bonds (Scheme 1a);
for example, the a-aminoxylation of alkenal 3 with nitroso-
benzene 4 and subsequent nucleophilic attack of the in situ
generated amine on Michael acceptor 2. Initially, we recog-
nized that a number of chemoselectivity issues needed to be
addressed: 1) In addition to a-aminoxylation the enamine
intermediate may undergo conjugate addition with another
molecule of the alkenal (Scheme 1b), which is known from
previous studies. 2) The aza-Michael addition step may be
competing with the undesired inter- or intramolecular nucle-
ophilic attack of the in situ generated amine to the aldehyde
(Scheme 1c).[10] 3) Central to the utility of this new domino
process is the mechanistic requirement that a chiral environ-
ment is established to control the aza-Michael addition and
the final asymmetric protonation (when R is not a hydrogen
atom). This control would ensure high levels of diastereose-
lectivity for the overall process, which is challenging because
of the flexibility of the acyclic substrate. To circumvent the
first two problems, a suitable electron-withdrawing group
[*] M. Lu, D. Zhu, Dr. Y. Lu, Y. Hou, B. Tan, Prof. Dr. G. Zhong
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University
21 Nanyang Link, Singapore 637371 (Singapore)
Fax: (+65)6791-1961
E-mail: guofu@ntu.edu.sg
[**] Research support from the Ministry of Education in Singapore
(ARC12/07, no. T206B3225) and Nanyang Technological University
(URC, RG53/07 and SEP, RG140/06) is gratefully acknowledged. We
thank Prof. Daiqian Xie for helpful discussions, and Dr. Yongxin Li
for the X-ray crystallographic analysis.
À
should be used on the Michael acceptor for the C N bond-
À
forming step while remaining effectively inert during the C O
bond-forming step. In terms of enantiocontrol, we also
envisioned that the aza-Michael addition and protonation
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200803731.
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would take place in a concerted manner by a preferred
transition state (see below).
Among the solvents tested, polar, protophobic acetonitrile
was found to be best with respect to the chemical yield and
optical purity (Table 1, entry 3). It is also noteworthy that
although 6a proved to be an excellent catalyst in the a-
aminoxylation, pyrrolidine-based tetrazole 6b[13] induced
reaction with lower conversion (Table 1, entry 7). Performing
the reaction with a larger excess of 3a led to complete
conversion, and 5a was isolated in 59% yield (Table 1,
entry 8). Having identified the optimal reaction medium, we
examined the temperature effect on the transformation.
Notably, considerable side reactions can be detected at 08C
(Table 1, entry 9), but suppression of the homodimerization
was accomplished at À208C (Table 1, entry 10). To avoid
making intractable byproducts, the reaction mixture was
diluted (Table 1, entry 11).
Nitroalkenes are among the most reactive Michael
acceptors,[11] so we started our investigation by using 3a
under the previously established conditions[7a] (nitroalkenal
3a (1.5 equiv), nitrosobenzene (1.0 equiv), and l-proline
(20 mol%) in DMSO). To our delight, the proposed domino
strategy was facile at room temperature and was complete
within 30 minutes (Table 1). The course of the reaction was
Table 1: Organocatalytic domino a-aminoxylation/aza-Michael reac-
tions: screening reaction conditions.[a]
Next, the effect of the catalyst loading was evaluated.
Remarkably, in the presence of tetraethylammonium bro-
mide (TEAB) (Table 1, entry 12)[14] a catalyst loading as low
as 0.5 mol% could be used without any loss in the ee values or
the d.r. numbers (Table 1, entry 14). For operational conven-
ience 5 mol% l-proline, under otherwise identical reaction
times, ensured high levels of reaction efficiency and enantio-
selectivity (Table 1, entry 13). Notably, after the in situ
reduction, the d.r. of the corresponding alcohol significantly
dropped to 90:10 (Table 1, entry 15), albeit the ee value was
not affected. This result implied that l-proline played an
important role in diastereocontrol.
Entry 6 (mol%) Solvent t [h]
Yield [%][b] ee [%][c]
d.r.[d]
1
6a (20)
6a (20)
6a (20)
6a (20)
6a (20)
6a (20)
6b (20)
6a (20)
6a (20)
6a (20)
6a (20)
6a (20)[i]
6a (5)[i]
6a (0.5)[i]
6a (20)[i]
DMSO
DMF
0.5
0.5
0.5
0.5
46
44
99
99
>99:1
>99:1
>99:1
>99:1
n.d.
2
3
4
5
CH3CN
CHCl3
THF
55
99
53
98
24
48
0.5
0.5
1
<20
<5
49
n.d.
n.d.
99
6
H2O
n.d.
7
CH3CN
CH3CN
CH3CN
CH3CN
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
90:10
We then explored the scope of these transformations by
using the optimized reaction conditions. The method was
applied to a variety of nitroalkenal substrates, and as shown in
8[e]
59
99
9[e,f]
10[e,g]
11[e,g]
12[e,g]
13[e,g]
14[e,g]
15[e,g]
63
67
73
90
>99
>99
>99
>99
>99
>99
>99
2
CH3CN 24[h]
CH3CN 14[h]
CH3CN 24[h]
CH3CN 72[h]
Table 2: Organocatalytic domino a-aminoxylation/aza-Michael reac-
tions: substrate scope.[a]
90
77
CH3CN
8[h]
88[j]
[a] Reaction conditions: 4a (1.0 equiv ; 1m), 3a (1.5 equiv), and catalyst
6 at room temperature (238C) in the indicated solvent. [b] Yield of
isolated product. [c] Determined by chiral HPLC analysis. [d] Determined
by 1H NMR methods. [e] Used 3 equiv of 3a. [f] Reaction was conducted
at 08C. [g] Reaction was conducted at À208C. [h] 0.1m of 4a. [i] Added
1.0 equiv of TEAB. [j] In situ reduction was performed using NaBH4 to
provide the corresponding alcohol. n.d.=not determined.
Entry
R
ArNO Yield [%][b]
ee [%][c]
d.r.[d]
1
2
3
4
5
6
7
8
H (3a)
H (3a)
H (3a)
Me (3b)
Me (3b)
Et (3c)
Et (3c)
Ph (3d)
4a
4b
4c
4a
4c
4a
4c
4a
4a
4c
4a
4c
4a
4c
4a
4c
4d
90 (5a)
79 (5b)
88 (5c)
75 (5d)
73 (5e)
68 (5 f)
60 (5g)
73 (5h)
50 (5i)
66 (5j)
47 (5k)
45 (5l)
78 (5m)
78 (5n)
75 (5o)
70 (5p)
90 (5q)
>99
97
>99
99
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
easily monitored by observing the change in the color of the
solution from green to orange. After the workup, pure THO
5a was isolated in 46% yield with 99% enantiomeric excess
(ee) and a diastereomeric ratio (d.r.) greater than 99:1
(Table 1, entry 1). This reaction led to the first successful
isolation of a stable aldehyde after the a-aminoxylation, and
the rare case of an inactivated amine undergoing a conjugate
addition with an aliphatic nitroalkene with high stereoinduc-
tion.[12] A preliminary screening indicated that the catalytic
activity and the asymmetric induction were dependent on the
solvent. Excellent enantio- and diastereoselectivities were
obtained in polar, protophilic solvents, such as DMSO and
DMF (Table 1, entries 1 and 2). A halogenated solvent
possessing a lower polarity was also tolerated (Table 1,
entry 4), whereas an ethereal solvent (THF) and water had
deleterious effects on the reactivity (Table 1, entries 5 and 6).
99
>99
>99
>99
>99
99
>99
>99
>99
>99
>99
99
9
Bn (3e)
Bn (3e)
10
11
12
13
14
15
16
17
pMeC6H4CH2 (3 f)
pMeC6H4CH2 (3 f)
pClC6H4CH2 (3g)
pClC6H4CH2 (3g)
pBrC6H4CH2 (3h)
pBrC6H4CH2 (3h)
H (3a)
>99
[a] Reaction conditions: 4a (1.0 equiv ; 0.1m), 3a (3.0 equiv), TEAB
(1.0 equiv ), and 6a (5 mol%) at À208C in CH3CN. [b] Yield of isolated
product. [c] Determined by chiral HPLC analysis. [d] Determined by
1H NMR methods.
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Table 3: Preliminary mechanistic investigations: catalysis of the aza-
Michael addition step.
Table 2 different substituents were well-tolerated at the
a position to the nitro group. The R group of component 3
ranges from simple to sterically demanding groups, as well as
valuable functional groups. Good yields were observed
although there was some fluctuation depending on the
substituents. The variation of the steric effects (Table 2,
entries 4–8) or the electronic effects (Table 2, entries 9–16)
had only a small impact on the introduction of the third chiral
center, which was evidenced by the uniformly high ee and
d.r. values. Furthermore, this method was applicable to
various aromatic nitroso compounds; for example, 2-methyl-,
4-methyl- and 4-bromo-nitrosobenzene (Table 2, entries 2, 3,
and 17). The fact that the R and R’ groups of precursors 3 and
4, respectively, can be varied demonstrates the versatility of
our approach.
Entry
Cat. (mol%)
T [8C]
t [h]
Conversion[b]
1
2
3
4
none
none
TEA (100)
quinine (20)
À20
RT
RT
48
48
48
18
n.r.
n.r.
31
RT
>95
[a] Reaction conditions: 7 (1.0 equiv, 0.1m), 8 (1.0 equiv), and the
corresponding catalyst at room temperature in CH3CN. [b] Determined
by 1H NMR methods. TBS=tert-butyldimethylsilyl; n.r.=no reaction.
This domino reaction generates up to three stereogenic
centers and forms only one out of eight possible stereoiso-
mers. The origin of the high stereoselectivity derives from the
a-aminoxylation reaction, which is known to proceed with
high enantioselectivity.[15] This selectivity is maintained in the
second step by going through a sterically favored transition
state (see below). The relative and absolute configurations of
reaction did not proceed after 2 days at À208C (Table 3,
entry 1). Elevating the temperature to room temperature
provided similar results (Table 3, entry 2), and when 1 equiv-
alent of TEA was used as a Lewis base in the reaction it
proceeded sluggishly with a 31% conversion. This experiment
revealed that the tertiary amine itself was not sufficient to
enhance the reactivity of 7 (Table 3, entry 3). The introduc-
tion of a hydrogen-bond donor,[17] 20 mol% of quinine,
resulted in full conversion within 18 hours. These observa-
tions indicate that the aza-Michael addition step is catalyzed
by hydrogen-bonding interactions. Combined with the fact
that intermediates cannot be detected in the 1H NMR spectra
recorded during the course of the reaction or upon product
isolation, a concerted mechanism is proposed. After the a-
aminoxylation step, the aza-Michael addition/protonation[18]
proceeds in a synergistic way and is assisted by a molecule of
water which participates in two hydrogen bonds; the hydro-
gen bonds are formed between the water molecule and both
the in situ generated amine moiety and the nitro group
(Figure 2). DFT calculations[19] of the lowest energy transition
state also confirm this assumption.
1
THO 5d were determined by H NMR nuclear Overhauser
effect (NOE) experiments and X-ray crystallography
(Figure 1) and compared with respective related a-amino-
xylations.[15,16]
Figure 1. X-ray crystal structure of 5d.[16]
Since the the aldehyde group and the a-methylnitro group
are trans and pointing away from each other in the crystal
structure of 5d , it is unlikely that l-proline participates in the
reaction by covalent bond catalysis in the transition state of
the aza-Michael addition/protonation step. To get some
mechanistic insight into this domino reaction, a series of
control experiments were carried out (Table 3).
We chose O-(tert-butyldimethylsilyl)-N-phenylhydroxyl-
amine (7) and (E)-(4-nitrobut-3-enyl)benzene (8) as mimics
of the in situ generated amine substrate and the nitroalkenyl
reactant, respectively. In the absence of any catalyst, the
Figure 2. DFT-calculated lowest energy transition state for the aza-
Michael addition/protonation in CH3CN.[19]
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Communications
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In summary, we have developed a novel, practical, and
enantio- and diastereoselective domino reaction for the
synthesis of functionalized THOs by using a simple amine
catalyst. The results disclosed herein demonstrate the ability
to control the regio- and stereochemistry of the reaction for
the synthesis of THOs from acyclic substrates. We anticipate
that a-aminoxylation directed domino reactions will have
great potential in the field of organocatalysis. The reaction,
which is easy to perform, proceeds cleanly with complete
stereocontrol and does not require a change in the reaction
conditions or adding reagents. This discovery is likely to be
used in synthetic applications, especially since the a-amino-
xylation reaction can be combined with existing domino
methods. Applications of this methodology to total syntheses
and detailed mechanistic studies will be described in due
course.
Received: July 31, 2008
Published online: October 7, 2008
Keywords: aminoxylation · asymmetric catalysis · cyclizations ·
domino reactions · organocatalysis
.
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[16] CCDC 670447 (5d) contains the supplemantary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambdridge Crystallographic Data Center via
www.ccdc.cam.ac.uk/data request/cif. The X-ray crystal struc-
ture of 5d showed the relative configuration. The absolute
configuration was assigned for the a-aminoxy carbon center as R
based on previous reports and mechanism studies. For reports,
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[19] For computational details, please see the Supporting Informa-
tion.
Angew. Chem. Int. Ed. 2008, 47, 10187 –10191
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www.angewandte.org 10191