Asymmetric one-pot synthesis of 1,3-oxazolidines and 1,3-oxazinanes via hemiaminal intermediates

Article abstract of DOI:10.1021/ol501789c

A highly efficient method for the enantioselective one-pot synthesis of 1,3-oxazolidines and 1,3-oxazinanes has been reported. The reaction proceeds via the formation of hemiaminal intermediates obtained by the enantioselective addition of respective alcohols to imines catalyzed by a chiral magnesium phosphate catalyst, followed by intramolecular cyclization under mildly basic conditions. A wide range of substrates have been converted to the respective chiral heterocyclic products in high yields and with excellent enantioselectivities using this one-pot procedure.

Full text of DOI:10.1021/ol501789c

Letter
pubs.acs.org/OrgLett
Open Access on 07/30/2015
Asymmetric One-Pot Synthesis of 1,3-Oxazolidines and
1,3‑Oxazinanes via Hemiaminal Intermediates
Sri Krishna Nimmagadda, Zuhui Zhang, and Jon C. Antilla*
Department of Chemistry, University of South Florida, 4202 East Fowler Avenue, CHE205A, Tampa, Florida 33620, United States
S
* Supporting Information
ABSTRACT: A highly efficient method for the enantiose-
lective one-pot synthesis of 1,3-oxazolidines and 1,3-
oxazinanes has been reported. The reaction proceeds via the
formation of hemiaminal intermediates obtained by the
enantioselective addition of respective alcohols to imines
catalyzed by a chiral magnesium phosphate catalyst, followed
by intramolecular cyclization under mildly basic conditions. A
wide range of substrates have been converted to the respective
chiral heterocyclic products in high yields and with excellent
enantioselectivities using this one-pot procedure.
hiral oxazolidines are important structural moieties that
1
Cexist in many biologically active compounds. The 1,3-
oxazolidine ring is present in polycyclic tetrahydroisoquinoline
alkaloids such as quinocarcin and its analogue terazomine, both
of which have antitumor activity.1,2 They are widely used in
asymmetric synthesis3 as chiral auxiliaries3a in reactions that
include cyclopropanation,3b Grignard reaction,3c epoxidation,3d
1,3-dipolar cycloadditions,3e intramolecular Diels−Alder reac-
tion,3f and hydrogenation.3g 1,3-Oxazolidines are also used as
chiral ligands for transition metal catalysts in asymmetric
catalysis.4 Generally, oxazolidines are prepared by the
Figure 1.
condensation of chiral 1,2-amino alcohols with aldehydes,
ketones, or oxo compounds.4 These methods involve the use of
chiral reagents and stoichiometric equivalents of catalysts. Yoon
et al. described copper catalyzed aminohydroxylation of
styrenes and oxyamination of olefins using an iron catalyst
cyclization through intramolecular nucleophilic substitution in
5-exo-tet fashion, in accordance with Baldwin’s rules.13
for the enantioselective synthesis of 1,3-oxazolidines.5 Recently,
Jarvo et al. developed transition metal catalyzed stereospecific
and stereoconvergent methods to synthesize chiral 1,3-
oxazolidines.6 In addition, Du and co-workers reported
rhodium catalyzed cycloaddition reactions of racemic butadiene
monoxide with imines.7 Wang et al. proposed an interesting
approach to synthesize benzoxazoles via organocatalytic [4 + 1]
annulation, but with poor enantiocontrol.8 Herein, we report
the chiral magnesium phosphate catalyzed asymmetric one-pot
synthesis of chiral 1,3-oxazolidines with high yields and
excellent enantioselectivity.
Intrigued by the reports of Ishihara,10a−c List,10d and the
recent results from our group on chiral BINOL phosphate-
s,10e−h,k we initiated optimization of the catalyst with the use of
chiral phosphoric acids and their metal phosphate complexes as
possible catalysts. Interestingly, 9-anthryl derived BINOL
phosphoric acid gave a very low ee (Table 1, entry 1). This
prompted us to explore alkali and alkaline-earth metal
complexes of chiral phosphates. Ca[P1]2 gave a good yield
but showed very poor selectivity (Table 1, entry 2), while with
Mg[P1]2 the product is formed with high yield and
enantioselectivity. We observed that a 3,3′-triisopropyl derived
BINOL phosphate metal complex also gave the product in high
yield and enantioselectivity. Clearly, Mg[P2]2 has proven to be
the best catalyst (Table 1, entry 5) with excellent selectivity,
whereas Ca, Li, Al, Zn, Sr complexes of the 3,3′-triisopropyl
Over the past decade, chiral phosphoric acids9 and metal
complexes of chiral phosphates10 have been used as effective
catalysts in various asymmetric transformations.11 In 2008, our
group reported the enantioselective addition of alcohols to
imines using 3,3′-9-anthryl-BINOL phosphoric acid.12 To
further expand the utility of this methodology, we envisioned
the possible synthesis of chiral 1,3-oxazolidines (Figure 1) by
Received: June 20, 2014
© XXXX American Chemical Society
A
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Letter
a
Table 1. Optimization of Reaction Conditions
b
c
entry
catalyst
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
H[P1]
73
91
90
70
90
94
90
95
98
7
10
95
68
97
66
40
74
74
Ca[P1]2
Mg[P1]2
Ca[P2]2
Mg[P2]2
Li[P2]2
Al[P2]3
Zn[P2]2
Sr[P2]2
a
Reaction conditions: 1a (1.0 equiv), 2 (2.0 equiv), 2.5 mol % catalyst,
b
ethyl acetate (1 mL), and 4 Å MS 40 mg/mL. Isolated yield.
c
Determined by chiral HPLC analysis.
Table 2. Optimization of Reaction Conditions for the
a
Intramolecular Cyclization
Figure 2. Catalytic asymmetric synthesis of 1,3-oxazolidines.
Experimental conditions: 1a (1.0 equiv), 2 (2.0 equiv), 2.5 mol %
catalyst, ethyl acetate, and 4 Å MS 40 mg/mL. Ethyl acetate was
removed before step 2, and DMF and Cs2CO3 (2.0 equiv) were added.
All yields are isolated. The ee was determined by chiral HPLC analysis.
b
c
c
entry
X
base
yield (%)
ee of 3 (%)
ee of 4a (%)
1
2
3
4
5
6
7
Cl
Cl
Cl
Br
Br
Br
Br
Cl
Cl
K3PO4
DBU
10
0
95
95
95
65
65
65
65
95
93
ND
ND
ND
ND
22
Cs2CO3
DMAP
DBU
0
0
82
86
90
71
97
2, entries 5,6). Interestingly, Cs2CO3 gave product 4a in high
yield retaining the selectivity (Table 2, entry 7).
KOtBu
Cs2CO3
KOtBu
Cs2CO3
57
65
d
To our delight, optimization of solvents using 3a with bases
of varied strength furnished the desired product in good yield.
With KOtBu as the base the reaction showed little loss in
selectivity, whereas Cs2CO3 at 0 °C produced 4a in high yield
with retention of selectivity. Presumably, a strong base would
also interact with the acidic proton on carbon and hence lower
the selectivity of the cyclized product. Clearly, cyclization of 3a
using Cs2CO3 in DMF is the ideal condition for the formation
of 4a in high yield with excellent enantioselectivity (entry 9).
To further investigate the scope of this reaction in one pot,
we performed the reaction from 3a to 4a in ethyl acetate as
solvent. Unfortunately, the reaction did not proceed to
completion (Table 2, entry 3). Alternatively, we tried the
transformation from 1a to 3a in DMF using optimized
conditions, but a racemic product was obtained. On the basis
of these observations, after formation of 3a, we concentrated
the reaction by removing the solvent and then added DMF and
8
e,f
84
9
93
a
Reaction Conditions: 3 (1.0 equiv), base (4.0 equiv), ethyl acetate.
Isolated yield. Determined by chiral HPLC analysis. THF used as
solvent. DMF used as solvent. Base added at 0 °C.
b
c
d
e
f
derived BINOL phosphate showed moderate enantioselectiv-
ities (entries 4, 6−9).
A brief screening of bases was performed for the intra-
molecular cyclization of 3a. We observed that K3PO4, DBU,
and Cs2CO3 in ethyl acetate did not lead to the cyclized
product 4a. By using the more reactive substrate 3b with
bromide as the leaving group, the desired transformation was
provided with bases DBU and KOtBu in good yields. But the
highest enantioselectivity we observed for 3b was 65% (Table
B
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental conditions, characterization data, and spectra for
all compounds. This material is available for free of charge via
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jantilla@usf.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Institutes of Health (NIH GM-082935)
and the National Science Foundation (NSF-0847108) for
financial support.
REFERENCES
■
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Under the optimized conditions, we examined a wide variety
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with excellent enantioselectivities (Figure 2). The results
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We further envisaged the possible synthesis of chiral 1,3-
oxazinanes14 using the optimized methodology. The hemi-
aminal intermediate formed by the addition of 3-chloropropa-
nol to 1a was obtained with high selectivity, but after
cyclization with Cs2CO3 a racemic product was observed. A
series of experiments were conducted with 3-chloropropanol
using different bases and different temperature variations which
showed no effect on retaining selectivity. To our delight, the
use of more reactive 3-bromopropanol favored the formation of
six membered products with moderate to good enantioselectiv-
ities and high yields. Both electron-releasing and -withdrawing
substituents on the phenyl ring were tolerated (Figure 3).
In summary, the one-pot synthesis of chiral 1,3-oxazolidines
and chiral 1,3-oxazinanes by 9-anthryl derived chiral BINOL
magnesium phosphate catalyzed enantioselective addition of
alcohol to imines followed by 5-exo-tet cyclization and 6-exo-tet
cyclization of hemiaminal intermediates under mild basic
conditions has been successfully achieved with high yields
and excellent enantioselectivities.
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