Highly efficient asymmetric synthesis of enantiopure dihydro-1,2-oxazines: Dual-organocatalyst-promoted asymmetric cascade reaction

Article abstract of DOI:10.1021/ol301218x

A one-pot dual-organocatalyst-promoted asymmetric α-aminoxylation/ aza-Michael/aldol consendation cascade reaction is presented. The targeted optically active 1,2-oxazine derivatives are synthesized in moderate yields (up to 70%), excellent enantioselectivities (ee >99% in all cases), and excellent diastereoselectivities (dr up to >99:1) under mild conditions. To further elucidate the synthetic utility of the cascade products, cleavage of the N-O bond is demonstrated and an enantiopure syn-1,4-amino alcohol derivative is achieved in excellent yield.

Full text of DOI:10.1021/ol301218x

ORGANIC
LETTERS
2012
Vol. 14, No. 15
3818–3821
Highly Efficient Asymmetric Synthesis
of Enantiopure Dihydro-1,2-oxazines:
Dual-Organocatalyst-Promoted
Asymmetric Cascade Reaction
Hua Lin, Yu Tan, Xing-Wen Sun,* and Guo-Qiang Lin*
Department of Chemistry, Fudan University, 220 Handan Lu, Shanghai 200433,
P. R. China
sunxingwen@fudan.edu.cn; lingq@sioc.ac.cn
Received May 3, 2012
ABSTRACT
A one-pot dual-organocatalyst-promoted asymmetric r-aminoxylation/aza-Michael/aldol consendation cascade reaction is presented. The
targeted optically active 1,2-oxazine derivatives are synthesized in moderate yields (up to 70%), excellent enantioselectivities (ee >99% in all
cases), and excellent diastereoselectivities (dr up to >99:1) under mild conditions. To further elucidate the synthetic utility of the cascade
products, cleavage of the NꢀO bond is demonstrated and an enantiopure syn-1,4-amino alcohol derivative is achieved in excellent yield.
Optically pure 1,2-oxazines have been used widely in the
construction of biologically active compounds1 and are
valuable chiral building blocks.2 Moreover, 1,2-oxazines
also possess synthetic utility via reductive NꢀO bond
cleavage to form highly functionalized 1,4-amino alcohols
which can be found in a number of bioactive natural
products. Recently, there has been great progress in the
synthesis of 1,2-oxazines.3 Whereas, there have been sev-
eral methods for the synthesis of chiral tetrahydro-1,2-
oxazines,3l,nꢀq only one general route was reported for the
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r
10.1021/ol301218x
Published on Web 07/18/2012
2012 American Chemical Society

construction of dihydro-1,2-oxazines by Ley’s group.3h,i It
was rationlized that R-oxyamination of an enamine inter-
mediate with nitrosobenzene4 was followed by nucleo-
philic attack on a vinyl phosphonium salt, which would
subsequently form a dihydro-1,2-oxazine through an in-
tramolecular Wittig process. However, attempts to extend
the reaction scope for this example are limited, and there-
fore the design and development of a practical, asymmetric
synthetic cascade procedure to access enantiopure function-
alized dihydro-1,2-oxazine from acyclic starting materials
is still highly desirable.
enantioselective transformations. They activate various
aldehydes by enamine formation (raising the HOMO) or
R,β-unsaturated aldehydes by iminium-ion formation
(lowering the LUMO).6 This ability allows the catalyst to
be ideally employed in cascade reactions, which proceed
consecutively and under the same reaction conditions to
construct complex frameworks from simple precursors.7
Herein, we report our effort towards organocatalytic
asymmetric assembly cascade reactions that provides an
entry to enantioenriched 1,2-oxazines in high diastereo-
and enantioselectivities.
Organocatalyzed cascade reactions which avoid time-
consuming and costly protection/deprotection processes
as well as the purification of intermediates represent a
flourishing area in organic chemistry.5 They can be applied
to generate useful enantiomerically pure building blocks
for the synthesis of biologically active natural products
with excellent stereoselectivity and are environmentally
friendly. Of all classes of structural organocatalysts, chiral
secondary amines are probably the most commonly used
to date and have shown excellent utility for a variety of
We envisioned that R-oxyamination of the aldehyde 1
with nitroso compound 2 catalyzed by a proline-based
secondary amine via an enamine process would yield I-1,
which underwent aza-Michael addition via the same cata-
lyst through an iminium process to provide the intermedi-
ate I-2, which then was subjected to an aldol condensation
again via enamine catalysis induced by the same amine to
finally afford trisubstituted functionalized dihydro-1,2-
oxazine molecular 4 with two newly formed chiral centers
(Scheme 1). However, three challenging issues affecting
chemoselectivities need to be addressed: (1) R-aminoxyla-
tion intermediate I-1 may itself oligomerize;8 (2) I-1 may
further react with another molecule of the excess aldehyde
1 in the presence of proline by aldol reaction; (3) the aza-
Michael addition step may be competing with the unde-
sired Michael reaction between the aldehyde 1 and R,β-
unsaturated aldehyde 3. If these side effects were overcome
and the desired transformations take place, we will be able
to develop a general, facile, cascade approach for the syn-
thesis of dihydro-1,2-oxazine. Herein, wereport our efforts
toward meeting these challenges.
(4) For aminoxylation of aldehydes, see: (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.
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2003, 44, 8293. For ketones, see: (d) Bøgevig, A.; Sunden, H.; Cordova,
A. Angew. Chem., Int. Ed. 2004, 43, 1109. (e) Hayashi, Y.; Yamaguchi,
J.; Sumiya, T.; Shoji, M. Angew. Chem., Int. Ed. 2004, 43, 1112. For a
review, see: (f) Yamamoto, H.; Momiyama, N. Chem. Commun. 2005,
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Biochemistry; Worth, NY, 1993. (b) Katz, L. Chem. Rev. 1997, 97, 2557.
(c) Koshla, C. Chem. Rev. 1997, 97, 2577. (d) Koshla, C.; Gokhale,
R. S.; Jacobsen, J. R.; Cane, D. E. Annu. Rev. Biochem. 1999, 68, 219.
(e) Mann, J. Chemical Aspects of Biosynthesis; Oxford Chemistry Primers,
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Prod. Rep. 2001, 18, 380. (g) Enders, D.; Grondal, C.; Huuttl, M. R. M.
Angew. Chem., Int. Ed. 2007, 46, 1570. (h) Yu, X.; Wang, W. Org.
Biomol. Chem. 2008, 6, 2037. (c) Alba, A.; Companyo, X.; Viviano, M.;
Rios, R. Curr. Org. Chem. 2009, 13, 1432. (d) Grondal, C.; Jeanty, M.;
Enders, D. Nat. Chem. 2010, 2, 167. (e) Mayano, A.; Rios, R. Chem. Rev.
2011, 111, 4703.
Scheme 1. Proposed Organocatalytic Cascade Reaction for the
Synthesis of Optically Dihydro-1,2-oxazines
(6) For selected reviews, see: (a) Ahrendt, K. A.; Borth, C. J.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243. (b) Northrup,
A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 2458. (c) List,
B. Chem. Commun. 2006, 819and references therein. (d) Mukherjee, S.;
Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471.
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(e) Erkkila, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416.
(f) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int.
Ed. 2008, 47, 6138. (g) MacMillan, D. W. C. Nature 2008, 455, 304.
(7) For selected reviews and papers of amine-catalyzed cascade
reactions, see: (a) Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem.
Commun. 2003, 551. (b) Wasilke, J.-C.; Obrey, S. J.; Baker, R. T.; Bazan,
G. C. Chem. Rev. 2005, 105, 1001. (c) Ramon, D. J.; Yus, M. Angew.
Chem. 2005, 117, 1628. Angew. Chem., Int. Ed. 2005, 44, 1602. (d) Guo,
H.-C.; Ma, J.-A. Angew. Chem. 2006, 118, 362. Angew. Chem., Int. Ed.
2006, 45, 354. (e) Tietze, L. F.; Brasche, G.; Gerike, K. Domino Reactions
in Organic Chemistry; Wiley-VCH: Weinheim, 2006. (f) Enders, D.; H€uttl,
M. R. M.; Grondal, C.; Raabe, G. Nature 2006, 441, 861. (g) Xie, H.; Zu, L.;
Li, H.; Wang, J.; Wang, W. J. Am. Chem. Soc. 2007, 129, 10886.
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Chem., Int. Ed. 2007, 46, 1101. (i) Zu, L.; Li, H.; Xie, H.; Wang, J.; Jiang,
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A.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7892.
(m) Michrowska, A.; List, B. Nat. Chem. 2009, 1, 225. (n) Zhang, X.;
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Our preliminary experiments were initiated by using
propanal 1a and nitrosobenzene 2a as model substrates,
DMSO as the solvent, and L-proline as the catalyst in the
first R-aminoxylation reaction.7a (E)-Hex-2-enal 3a was
selected as the model of R,β-unsaturated aldehyde in
the second step and was added to the R-aminoxylation
(8) Products of the R-aminoxylation of aldehydes aren’t stable and
can’t be isolated in pure form because there are reactions that occurr
between the aldehyde and the amino groups in the products (existing in
the form of oligomers), therefore in situ reduction of the aldehydes to the
corresponding alcohols is necessary to obtain pure products. For an
example, see: Hayashi, Y.; Yamaguchi, J.; Sumiya, T.; Hibino, K.; Shoji,
M. J. Org. Chem. 2004, 69, 5966.
Org. Lett., Vol. 14, No. 15, 2012
3819

reaction mixture until all the nitrosobenzene 2a was
consumed. Pleasingly, the cascade process proceeded
smoothly to afford the desired product 4a albeit with a
complicated reaction mixture (Table 1, entry 1; 8%
yield, dr = 52:48, ee >99%). Although proline has been
reported to be an excellent enamine catalyst,9 this amino
acid is generally ineffective as an iminium catalyst10 in the
case of enals. Given these mutual reactivity profiles, we
hypothesized that the combination of the readily available
R, R-disubstituents prolinol trimethylsilyl ether catalyst 6a
or 6b and proline should serve as a dual-catalyst system11
that fully satisfied the chemoselective requirements for
cycle-specific catalysis. As we predicted, the combina-
tion of catalyst 6a and proline provided a better yield
(20%) and dr (81:19), with no loss in enantioselectivity
(ee >99%) (Table 1, entry 2). And the combination of the
secondary amine with a strong electron-withdrawing
substituent on the aryl rings of catalyst 6b and proline
gave a diminished result (Table 1, entry 3). To improve the
yield, we resized the loading of the iminium catalyst 6a to
accelerate the aza-Michael reaction (Table 1, entry 4).
Among the screened solvents (CHCl3,7b CH3CN,7c etc.),
CHCl3 proved to be the proper choice giving the best
chemical yield and diastereoselectivity (Table 1, entries
5ꢀ6). We next examined the additive and ratio (both the
ratio of catalysts and reagents) effectofthisnewly designed
cascade transformation (Table 1, entries 7ꢀ10). Finally,
the best conditions were established: First, R-aminoxyla-
tionwas conducted at0 °C, and then the aza-Michael/aldol
condensation was conducted at room temperature, cata-
lyzed by a dual-catalyst combination system [L-proline
(10 mol %) and catalyst 6a (30 mol %)], with AcOH
(0.3 equiv) and 4 A MS (100 mg) as additives and CHCl3 as
the solvent (Table 1, entry 10).
With the optimal reaction conditions in hand (Table 1,
entry 10), the scope of this cascade reaction was investi-
gated. A variety of aldehydes for the first R-aminoxylation
were investigated. Butyraldehyde and 3-methylbutanal
gave better results, with a 62% and 58% yield, dr = 96:4
and 97:3 respectively (Table 2, entries 2ꢀ3). A long chain
aliphatic aldehyde, such as nonanal, is also a good sub-
strate, providing the desired 1,2-oxazine product in good
yield (Table 2, entry 4). Linear aliphatic aldehydes bear-
ing some functional group such as OTs can be applied as
substrates in the domino reaction as well (Table 2, entry 5).
As the para-substituent of the phenyl ring of nitrosoben-
zene, either an electron-donating or -withdrawing group
can be successfully employed to afford 1,2-oxazine deriva-
tives in good yield (59ꢀ62%) with excellent diastereoselec-
tivities (dr = 96:4) (Table 2, entries 6ꢀ8). Furthermore,
this method was applicable to various R,β-unsaturated
aldehydes. (E)-Pent-2-enal and (E)-dec-2-enal are suitable
substrates (Table 2, entries 9ꢀ10). To our delight, with
Table 1. Optimization of the Reaction Conditionsa
entry
sol.
cat. I
cat. II
t (h)
yieldb
drc
1
2
DMSO
DMSO/
DCM
30%
30%
ꢀ
4
4
8%
52:48
81:19
6a/
20%
20%
6b/
3
DMSO/
DCM
30%
20%
20%
20%
10%
10%
10%
10%
4
12
12
12
12
12
24
24
15%
24%
13%
22%
14%
24%
34%
44%
57:43
82:18
84:16
92:8
20%
6a/
4
DMSO/
DCM
30%
6a/
5
CH3CN
30%
6a/
6e
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
30%
6a/
7e
94:6
20%
6a/
8e,f
9e,g,h
10e,g,i
96:4
20%
6a/
96:4
20%
6a/
96:4
30%
a The reaction was performed using nitrosobenzene 2a (0.5 mmol,
1 M), aldehyde 1a (0.6 mmol), R,β-unsaturated aldehyde 3a (1.0 mmol)
and catalyst proline and 6 in indicated solvent. See Supporting Informa-
tion for details. b Isolated yield of product 4a. c Determined by 1H NMR
of the crude product. d For the determination of ee, see Supporting
Information. e The first R-aminoxylation was conducted at 0 °C. f The
reaction was performed using aldehyde 1a (1.5 mmol). g AcOH (0.2 equiv)
and 4 A MS (100 mg) were added. h The reaction was performed using
aldehyde 1a (1.5 mmol) and R,β-unsaturated aldehyde 3a (2.5 mmol) .
i AcOH (0.3 equiv) and 4 A MS (100 mg) were added.
(E)-ethyl 4-oxobut-2-enoate as the Michael acceptor and
butyraldehyde or 3-methylbutanal as the R-aminoxylation
aldehyde, the domino reaction proceeded smoothly, pro-
viding the desired 1,2-oxazine derivatives in good yields,
70% and 54%, respectively, with excellent diastereomeric
ratios of greater than 99:1 (Table 2, entries 11ꢀ12). It is
worth noting that aromatic R,β-unsaturated aldehydes can
be employed in this reaction system, but the desired
product coincidentally has the same polarity as the reagent
R,β-unsaturatedaldehydesleading todifficultyinthe isola-
tion of the desired 1,2-oxazine product by column chro-
matography, even with further reduction of the desired
aldehyde to the corresponding alcohol. Only when utiliz-
ing the aromatic R,β-unsaturated aldehydes with a CF3
group at the para-position on the phenyl ring, the product
could be isolated in 37% yield still with excellent diaster-
eoselectivity (Table 2, entry 13). It should be mentioned
that, in all cases, the enantiomeric excess ismorethan99%.
The absolute configuration of the cascade reaction
product was identified unambiguously through X-ray
(9) (a) List, B. Acc. Chem. Res. 2004, 37, 548. (b) Mukherjee, S.;
Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471.
(10) For a review of iminium catalysis, see: Lelais, G.; MacMillan, D.
W. C. Aldrichimica Acta 2006, 39, 79.
(11) Simmons, B.; Walji, A. M.; MacMillan, D. W. C. Angew. Chem.,
Int. Ed. 2009, 48, 4349.
3820
Org. Lett., Vol. 14, No. 15, 2012

Table 2. Synthesis of Chiral Dihydro-1,2-oxazinea
entry
1
R1, R2, R3
4
yield (%)b
44
drc
R1 = Me, R2 = Ph,
R3 = n-Pr
4a
96:4
2
3
4
5
6
R1 = Et, R2 = Ph,
R3 = n-Pr
4b
4c
4d
4e
4f
62
58
51
33
60
96:4
97:3
95:5
98:2
96:4
R1 = i-Pr, R2 = Ph,
R3 = n-Pr
Figure 1. X-ray crystal structure of the enantiomerically pure
(R)-N-tert-butylsulfinyl imine derivate.
R1 = n-Hep, R2 = Ph,
R3 = n-Pr
R1 = TsOC3H6,
R2 = Ph, R3 = n-Pr
R1 = i-Pr,
Scheme 2. NꢀO Cleavage
R2 = 4-BrC6H4,
R3 = n-Pr,
R1 = i-Pr,
7
8
4g
4h
59
62
>99:1
96:4
R2 = 4-MeOC6H4,
R3 = n-Pr
R1 = i-Pr,
R2 = 4-ClC6H4,
R3 = n-Pr
active nonproteinogenic analogues. Thus, our route pro-
vides an easy access to a potentially diverse set of such
compounds (Scheme 2).
9
R1 = i-Pr, R2 = Ph,
R3 = Et
4i
35
50
70
54
37
96:4
95:5
10
11
12
13
R1 = i-Pr, R2 = Ph,
R3 = n-Hep
4j
In summary, we have developed a dual-organocatalyst-
promoted asymmetric R-aminoxylation/aza-Michael/
aldol consendation cascade reaction for the synthesis of
chiral 1,2-oxazine derivates in good yield (up to 70%),
with excellent enantio- (ee >99% in all cases) and diaster-
eoselectivities (dr up to >99:1) under mild conditions.
Notably, a multifunctional chiral syn-1,4-amino alcohol
derivative could be prepared readily from the 1,2-oxazine
derivates. We are currently investigating the catalytic
mechanism of the cascade reaction and the application of
this methodology to asymmetric syntheses of some natural
and natural-like compounds and will be reporting the
results in due course.
R1 = i-Pr, R2 = Ph,
R3 = COOEt
4k
4l
>99:1
>99:1
>99:1
R1 = Et, R2 = Ph,
R3 = COOEt
R1 = i-Pr, R2 = Ph,
R3 = 4-CF3C6H4
4m
a The reaction was performed using nitrosobenzene 2 (0.5 mmol,
1 M), aldehyde 1 (1.5 mmol), R,β-unsaturated aldehyde 3 (2.5 mmol),
proline (10 mol %), catalyst 6a (30 mol %), AcOH (0.3 equiv), and 4 A
MS (100 mg) in CHCl3. See Supporting Information for details. b Yield
of isolated product 4. c Determined by 1H NMR of the crude product.
d For the determination of ee, see Supporting Information.
crystallographic analysis of (R)-N-tert-butylsulfinyl imine
derivate 7a derived from the corresponding adduct 4a
(Figure 1).
Acknowledgment. Financial support from the National
Natural Science Foundation of China (21072031 and
20802009) and the Shanghai Municipal Committee of
Science and Technology (10ZR1404100) is greatly
acknowledged.
With optically pure 1,2-oxazines obtained, we next
demonstrated the synthetic utility of the cascade products.
Reduction of the 1,2-oxazine product 4a with NaBH4, fol-
lowed by NꢀO bond hydrogenolysis by the Zn/HCl sys-
tem, provides the corresponding valuable syn-1,4-amino
alcohol derivative8ain91%yieldintwo steps, withoutany
loss of enantioselectivity (ee >99%). Because 1,4-amino
alcohols are found extensively in nature and are a chiral
building block, they are potentially useful for the prepara-
tion of conformationally restricted peptides and biologically
Supporting Information Available. Experimental pro-
cedures and characterization data; copies of H and 13
1
C
NMR spectra and HPLC profiles. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 15, 2012
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