A highly stereoselective organocatalytic tandem aminoxylation/aza-Michael reaction for the synthesis of tetrahydro-1,2-oxazines

Article abstract of DOI:10.1021/ol801864c

(Chemical Equation Presented) A facile stereoselective synthesis of multifunctionalized tetrahydro-1,2-oxazines (THOs) has been achieved by the organocatalyzed asymmetric tandem α-aminoxylation/aza-Michael reaction for the C-O/C -N bond formations in moderate to good yields with excellent diastereo- (>99:1 dr) and enantioselectivities (92% to >99% ee).

Full text of DOI:10.1021/ol801864c

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4585-4588
A Highly Stereoselective Organocatalytic
Tandem Aminoxylation/Aza-Michael
Reaction for the Synthesis of
Tetrahydro-1,2-Oxazines
Di Zhu, Min Lu, Pei Juan Chua, Bin Tan, Fei Wang, Xinhao Yang,† and
Guofu Zhong*
DiVision of Chemistry and Biological Chemistry, School of Physical &
Mathematical Sciences, Nanyang Technological UniVersity, 21 Nanyang Link,
Singapore 637371, Singapore
guofu@ntu.edu.sg
Received August 10, 2008
ABSTRACT
A facile stereoselective synthesis of multifunctionalized tetrahydro-1,2-oxazines (THOs) has been achieved by the organocatalyzed asymmetric
tandem r-aminoxylation/aza-Michael reaction for the C-O/C-N bond formations in moderate to good yields with excellent diastereo- (>99:1
dr) and enantioselectivities (92% to >99% ee).
One of the most intensely studied areas in chemical synthesis
at present is the development of new catalytic and highly
enantioselective processes, particularly to generate useful
structural components present in biologically active natural
product.1 Asymmetric organocatalyses, especially with L-
proline and its derivatives, have witnessed marked progress
in a variety of reactions such as aldol,2 Mannich,3 Michael,4
Diels-Alder,5 R-amination,6 and R-aminoxylation reactions.7
Although much research has been devoted to the field of
carbon-carbon bond formation, the search for new methods
to stereoselectively generate the C-O and C-N bonds for
preparation of certain heterocyclic systems is still a significant
challenge in organic chemistry. Tetrahydro-1,2-oxazine
† Current address: Memstar Pte Ltd, 10 Science Park Road, No. 02-10,
The Alpha Building, Singapore 117684.
(1) (a) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem.,
Int. Ed. 2006, 45, 7134. (b) Yamamoto, Y.; Momiyama, N.; Yamamoto,
H. J. Am. Chem. Soc. 2004, 126, 5962.
(3) (a) Hayashi, Y.; Tsuboi, W.; Ashimine, I.; Urushima, T.; Shoji, M.;
Sakai, K. Angew. Chem., Int. Ed. 2003, 42, 3677. (b) List, B.; Pojarliev,
P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827. (c)
Cordova, A.; Watanabe, S.; Tanaka, F.; Notz, W.; Barbas, C. F., III. J. Am.
Chem. Soc. 2002, 124, 1866. (d) Cordova, A.; Notz, W.; Zhong, G.;
Betancort, J. M.; Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124, 1842. (e)
List, B. J. Am. Chem. Soc. 2000, 122, 9336.
(2) (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc.
2000, 122, 2395. (b) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III.
J. Am. Chem. Soc. 2001, 123, 5260. (c) Chowdari, N. S.; Ramachary, D. B.;
Cordova, A.; Barbas, C. F., III. Tetrahedron Lett. 2002, 43, 9591. (d)
Momiyama, N.; Torii, H.; Saito, S.; Yamamoto, H. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5374. (e) Northrup, A. B.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2002, 124, 6798. (f) Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.;
Gong, L.-Z.; Qiao, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. J. Am. Chem. Soc. 2003,
125, 5262. (g) Pidathala, C.; Hoang, L.; Vignola, N.; List, B. Angew. Chem.,
Int. Ed. 2003, 42, 2785.
(4) (a) Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2003, 125, 1192. (b) Betancort, J. M.; Barbas, C. F., III. Org.
Lett. 2001, 3, 3737.
(5) (a) Ramachary, D. B.; Chowdari, N. S.; Barbas, C. F., III. Angew.
Chem., Int. Ed. 2003, 42, 4233. (b) Juhl, K.; Jorgensen, K. A. Angew. Chem.,
Int. Ed. 2003, 42, 1498. (c) Northrup, A. B.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2002, 124, 2458.
10.1021/ol801864c CCC: $40.75
Published on Web 09/13/2008
2008 American Chemical Society

derivatives occur frequently in biologically active com-
pounds8 and are valuable synthetic intermediates.9 Not only
do they have the potential to act as therapeutic agents and
chiral building blocks, they also possess synthetic utility
through reductive N-O bond cleavage to form highly
functionalized 1,4-amino alcohols which can be found in a
number of bioactive natural products.
The nitroso function is recognized as a unique source to
prepare nitrogen- and oxygen-containing molecules. Various
catalytic asymmetric reactions exploiting the unique proper-
ties of nitroso compounds,10 such as aminoxylation,7 oxyam-
ination,11 and nitroso Diels-Alder reactions,12 have recently
been developed.
with complete control of both regio- and stereochemistry.1b
However, a direct tandem R-aminoxylation/aza-Michael
reaction of aldehydes has not been reported yet. Herein, we
describe a highly diastereo- and enantioselective tandem
aminoxylation /aza-Michael reaction of aldehydes bearing a
remote enemalonate as Michael acceptor at the δ-position
for the synthesis of functionalized tetrahydro-1,2-oxazines
(THOs) (Scheme 1), among which both C-O and C-N
bonds were formed in excellent stereoselectivity.
Scheme 1. Synthetic Strategy
In 2003, our group first reported the L-proline catalyzed
asymmetric R-aminoxylation of aldehydes with excellent
enantioselectivity.7a This methodology provides an easy
access to the enantioselective installation of a C-O bond.
Conjugate addition of amines or their synthetic equivalents
to R,ꢀ-unsaturated compounds constitutes one of the most
interesting methods for the C-N bond formation due to
the resulting ꢀ-amino adducts being privileged structures
found in natural products and used in the pharmaceutical
industry.13 Despite the importance of this methodology,
catalytic enantioselective aza-Michael reactions remain
elusive and can thus be considered a challenging task.14
In 2004, Yamamoto et al. reported an enantioselective
tandem O-nitroso aldol/Michael reaction with cyclic R,ꢀ-
unsaturated ketones to produce nitroso Diels-Alder adducts
We started our investigation using our previously
established conditions: nitrosobenzene (0.1 mmol, 1.0
equiv) and dimethyl 2-(5-oxopentylidene)malonate (0.12
mmol, 1.2 equiv) were added to 20 mol % L-proline in
1.0 mL of DMSO. To our delight, the proposed organo-
catalytic tandem aminoxylation/aza-Michael reaction was
indeed facile at room temperature and can be accomplished
within 30 min. The reaction progress can be easily
monitored by observation of its color change from green
to orange. After workup, the desired cyclic product was
isolated in 37% yield with excellent enantioselectivity
(98% ee) and diastereoselectivity (>99:1 dr) (Table 1,
entry 1). Furthermore, various catalysts and solvents were
surveyed and summarized in Table 1. The reaction
proceeded smoothly in the presence of pyrrolidinyl
tetrazole II or thiazolidine-4-carboxylic acid III to afford
the cycloadduct in a slightly lower yield and without any
loss in the ee and dr values (Table 1, entries 2 and 3).
Unfortunately, Jørgenson’s catalyst IV cannot be em-
ployed in this reaction to afford the corresponding
R-aminoxylation/aza-Michael product. L-Proline was cho-
sen as the catalyst not only because it is abundant and
cheap, but more importantly because of its efficiency
among all the other investigated catalysts. The screening
(6) (a) Chowdari, N. S.; Ramachary, D. B.; Barbas, C. F., III. Org. Lett.
2003, 5, 1685. (b) List, B. J. Am. Chem. Soc. 2002, 124, 5656.
(7) (a) Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247. (b) Brown,
S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc.
2003, 125, 10808. (c) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji, M.
Tetrahedron Lett. 2003, 44, 8293. (d) Hayashi, Y.; Yamaguchi, J.; Sumiya,
T.; Shoji, M. Angew. Chem., Int. Ed. 2004, 43, 1112. (e) Bøgevig, A. M.;
Sundeen, H.; Cordova, A. Angew. Chem., Int. Ed. 2004, 43, 1109. (f)
Mathew, S. P.; Iwamura, H.; Blackmond, D. G. Angew. Chem., Int. Ed.
2004, 43, 3317. (g) Cheong, P. H.-Y.; Houk, K. N. J. Am. Chem. Soc.
2004, 126, 13912. (h) Iwamura, H.; Wells, D. H., Jr.; Mathew, S. P.;
Klussmann, M.; Armstrong, A.; Blackmond, D. G. J. Am. Chem. Soc. 2004,
126, 16312. (i) Zhong, G. Chem. Commun. 2004, 606. (j) Zhong, G.; Yu,
Y. Org. Lett. 2004, 6, 1637. (k) Ramachary, D. B.; Barbas, C. F., III. Org.
Lett. 2005, 7, 1577. (l) Kumarn, S.; Oelke, A. J.; Shaw, D. M.; Longbottom,
D. A.; Ley, S. V. Org. Biomol. Chem. 2007, 5, 2678. (m) Zhu, X.; Tanaka,
F.; Hu, Y.; Heine, A.; Fuller, R.; Zhong, G.; Olson, A. J.; Lerner, R. A.;
Barbas, C. F., III.; Wilson, I. A. J. Mol. Biol. 2004, 343, 1269.
(8) (a) Uchida, I.; Takase, S.; Kayakiri, H.; Kiyoto, S.; Hashimoto, M.
J. Am. Chem. Soc. 1987, 109, 4108. (b) Terano, H.; Takase, S.; Hosoda, J.;
Kohsaka, M. J. Antibiot. 1989, 42, 145. (c) Yu, Q.-S.; Zhu, X.; Holloway,
H. W.; Whittaker, N. F.; Brossi, A.; Greig, N. H. J. Med. Chem. 2002, 45,
3684. (d) Katoh, T.; Itoh, E.; Yoshino, T.; Terashima, S. Tetrahedron 1997,
53, 10229. (e) Judd, T. C.; Williams, R. M. Angew. Chem., Int. Ed. 2002,
41, 4683. (f) Suzuki, M.; Kambe, J.; Tokuyama, H.; Fukuyama, T. Angew.
Chem., Int. Ed. 2002, 41, 4686.
(9) (a) Pulz, R.; Al-Harrasi, A.; Reissig, H.-U. Org. Lett. 2002, 4, 2353.
(b) Tishkov, A. A.; Reissig, H.-U.; Ioffe, S. L. Synlett 2002, 863. (c)
Buchholz, M.; Reissig, H.-U. Eur. J. Org. Chem. 2003, 3524. (d) Al-Harrasi,
A.; Reissig, H.-U. Angew. Chem., Int. Ed. 2005, 44, 6227. (e) Carson, C. A.;
Kerr, M. A. Angew. Chem. Int. Ed. 2006, 45, 6560.
(10) Palomo, C.; Vera, S.; Velilla, I.; Mielgo, A. Angew. Chem., Int.
Ed. 2007, 46, 8054.
(14) (a) Fustero, S.; Jimenez, D.; Moscardo, J.; Catalan, S.; del Pozo,
C. Org. Lett. 2007, 9, 5283. (b) Ibrahem, I.; Rıos, R.; Vesely, J.; Zhao,
G.-L.; Cordova, A. Chem. Commun. 2007, 849. (c) Vesely, H.; Ibrahem,
I.; Zhao, G.-L.; Rıos, R.; Cordova, A. Angew. Chem., Int. Ed. 2007, 46,
778. (d) Sunden, H.; Rıos, R.; Ibrahem, I.; Zhao, G.-L.; Eriksson, L.;
Cordova, A. AdV. Synth. Catal. 2007, 349, 827. (e) Vesely, J.; Ibrahem, I.;
Rıo´s, R.; Zhao, G.-L.; Xu, Y.; Cordova, A. Tetrahedron Lett. 2007, 48,
2193. (f) Li, H.; Wang, J.; Xie, H.; Zu, L.; Jiang, W.; Duesler, E. N.; Wang,
W. Org. Lett. 2007, 9, 965. (g) Chen, Y. K.; Yoshida, M.; McMillan,
D. W. C. J. Am. Chem. Soc. 2006, 128, 9328. (h) Gerasyuto, A. I.; Hsung,
R. P.; Sydorenko, N.; Slafer, B. W. J. Org. Chem. 2005, 70, 4248.
(11) (a) Momiyama, N.; Yamamoto, H. Org. Lett. 2002, 4, 3579. (b)
Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 5360. (c)
Guo, H.-M.; Cheng, L.; Cun, L. F.; Gong, L.-Z.; Mi, A. Q.; Jiang, Y.-Z.
Chem. Commun. 2006, 429. (d) Kano, T.; Ueda, M.; Takai, J.; Maruoka,
K. J. Am. Chem. Soc. 2006, 126, 5360.
(12) Wabnitz, T. C.; Saaby, S.; Jorgensen, K. A. Org. Biomol. Chem.
2004, 2, 828.
(13) EnantioselectiVe Synthesis of ꢀ-Amino Acids, 2nd ed.; Juaristi, E. C.,
Soloshonok, V. A., Eds.; Wiley-VCH Ltd.: New York, 2005.
4586
Org. Lett., Vol. 10, No. 20, 2008

Table 1. Catalyst and Solvent Screening in Tandem
Table 2. Optimized Conditions for the Tandem Aminoxylation/
Aminoxylation/Aza-Michael Reactiona
Aza-Michael Reactiona
temp
(°C)
cat.
(%)c
yield
(%)d
ee
(%)e
entry
equivb
time
dre
1
2
3
4
5
6
7
8
9f
1.2
1.2
1.2
1.5
2
3
3
3
3
23
0
20
20
20
20
20
20
10
5
1 h
3 h
52
61
65
69
73
79
84
72
73
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
1:1
98
98
98
98
98
98
98
98
nd
yield
ee
entry
cat.
solvent
time
(%)b
drc
(%)c
-20
-20
-20
-20
-20
-20
-20
24 h
18 h
16 h
13 h
18 h
24 h
24 h
1
2
3
4
5
6
7
8
9
I
DMSO
CH3CN
DMSO
CHCl3
CH3CN
CHCl3
DMF
NMP
THF
DCM
H2O
20 min
60 min
45 min
60 min
60 min
60 min
45 min
45 min
3 h
37
34
32
<10
52
46
41
45
<20
31
<10
>99:1
>99:1
>99:1
nd
>99:1
>99:1
>99:1
>99:1
nd
98
97
98
nd
98
98
98
98
nd
98
nd
II
III
IV
I
I
I
I
I
I
I
10
a Conditions: nitrosobenzene (0.1 mmol) was added to the solution of
aldehyde and catalyst in 1 mL of CH3CN at -78 °C, then stirred at various
temperatures. b Equiv is mol ratio of aldehyde/nitrosobenzene. c Catalyst
loading ) proline/nitrobenzene. d Isolated yields. e Ee and dr determined
by HPLC employing a Daicel Chiracel AS-H column. f Reduction in situ
was performed to provide the corresponding alcohol. Dr was determined
10
60 min
24 h
>99:1
nd
11d
1
by H NMR.
a In all cases, 0.2 equiv of catalyst was used in 0.1 M of nitrosobenzene
solution. b Isolated yields. c Ee and dr determined by HPLC employing a
Daicel Chiracel AS-H column. d 2 equiv of PTC added, PTC ) tetraethy-
lammonium bromide.
We further explored the generality of the reaction. The
optimized reaction condition was applicable for reactions of
various aromatic nitroso compounds 2a-h and some 2-(5-
oxopentylidene) malonate derivatives 1a-g, to give moderate
to good yields (52-84%) in excellent ee values (92-99%)
and dr values (>99:1). The 2-methyl substituent in nitroso-
toluene introduced more steric hindrance in the Michael
addition step and this may account for the decrease in ee
values (from 98% to 94% ee) when compared to the other
nitrosobenzene derivatives. We observed that the substitutents
in malonate also affected the yield of the Michael adducts.
Isopropyl substituent, being more sterically hindered than
propyl groups, generally gave low yields when compared
with that of propyl substituents (Table 3, entries 10-11,
16-17, and 20-21). The reason why dipentyl 2-(5-oxopen-
tylidene) malonate gave the worst result remains unknown
(Table 3, entry 13).
of various solvents revealed that CH3CN is the best solvent
as it gave the highest yield (52%) and without any loss
of enantio- or diastereoselectivities (Table 1, entry 5).
Halogenated solvent CHCl3 (Table 1, entry 6) and highly
polar and protophilic solvents, such as DMF and NMP
(Table 1, entries 7 and 8), gave relatively lower yields
(41-46%) whereas a less polar ethereal solvent, such as
THF (Table 1, entry 9), and the most polar solvent water
showed a deleterious effect on reactivity even after
addition of tetraethyl ammonium bromide as PTC and
stirring for 24 h (Table 1, entry 11).
Having established the choice of catalyst, we moved on
to screen the reaction temperatures. We observed that when
the reaction temperature decreased from room temperature
to -20 °C (Table 2, entries 1-3), the supression of both
side reaction and homodimer formation led to an increase
in yield (from 52% to 65%) and without any loss in the ee
and dr values. Increasing the equivalence of aldehyde to
nitrosobenzene from 1.2 to 3 equiv increased the yield from
65% to 79% and at the same time decreased the reaction
time from 24 h to 13 h. (Table 2, entries 3-6). Lastly, when
we decreased the catalyst loadings from 20 to 5 mol %, the
highest yield was found when 10 mol % of L-proline was
used (Table 2, entries 6-8). In terms of operational con-
venience, 10 mol % of L-proline ensured high levels of
reaction efficiency and enantioselectivity and was thus used
in the next reaction. It is also noteworthy that after in situ
reduction, the dr of corresponding alcohol product dropped
significantly to 1:1 (Table 2, entry 9).
To determine the stereochemistry of the tandem ami-
noxylation/aza-Michael reaction, a (2,4-dinitrophenyl)
hydrazine derivative 4i of the aldehyde product 3i was
synthesized (Scheme 2). The relative configuration of the
Scheme 2. Synthesis of Hydrazine Derivative
Org. Lett., Vol. 10, No. 20, 2008
4587

Table 3. Reaction Scope of the Tandem Aminoxylation/
Aza-Michael Additiona
entry
R1
R2
product yield (%)b
drc ee (%)c
>99:1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Me
Me
Me
Me
Me
Me
Me
Me
Et
H
3a
3b
3c
3d
3e
3f
84
70
63
73
65
62
72
52
73
81
69
79
67
71
73
72
69
71
67
74
67
71
98
94
98
99
98
99
99
99
99
99
99
99
92
99
95
98
96
96
99
99
99
99
2-Me
3-Me
4-Me
3-Cl
4-Cl
4-Br
4-OPh
H
>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
>99:1
>99:1
>99:1
>99:1
Figure 1. X-ray crystal structure of 4i.
3g
3h
3i
established by comparing it with the sterogenic center
generated by the aminoxylation step based on the relative
configuration of 4i and the known chemistry7 of the
aminoxylation.
In summary, we have reported the first highly diastereo-
and enantioselective approach for the synthesis of these
functionalized tetrahydro-1,2-oxazines via an organocata-
lyzed asymmetric tandem aminoxylation/aza-Michael reac-
tion. Further applications of this functionalized THOs to other
synthetically useful transformations are underway.
Pr
H
H
H
H
3j
3k
3l
i-Pr
Bu
Pen
Hex
Et
3m
3n
3o
3p
3q
3r
3s
3t
H
2-Me
2-Me
Pr
i-Pr 2-Me
Bu
Et
Pr
i-Pr 4-Br
Bu 4-Br
2-Me
4-Br
4-Br
Acknowledgment:This research was supported by the
Ministry of Education in Singapore (ARC12/07, no.
T206B3225) and Nanyang Technological University (URC,
RG53/07 and SEP, RG140/06). We thank Dr. Yongxin Li
in Nanyang Technological University for the X-ray crystal-
lographic analysis.
3u
3v
a Conditions: Nitrosobenzene (0.1 mmol) and L-proline (0.01 mmol)
were added to the solution of aldehyde (0.3 mmol) in 1 mL of CH3CN at
-78 °C, then stirred at -20 °C. b Isolated yields. c Ee and dr determined
by HPLC employing a Daicel Chiracel AS-H or AD-H column (see the
Supporting Information).
Supporting Information Available: Experimental pro-
cedures, characterization, spectra, chiral HPLC conditions
and X-ray crystallographic data (CIF file). This material is
available free of charge via the Internet at http://pubs.acs.org.
(2,4-dinitrophenyl) hydrazone 4i was then determined by
X-ray crystallography (Figure 1). The R configuration of
the chiral center created by the Michael addition was
OL801864C
4588
Org. Lett., Vol. 10, No. 20, 2008