Chiral phosphoric acid catalyzed addition of dihydropyrans to N -acyl imines: Stereocontrolled access to enantioenriched spirocyclic oxazoletetrahydropyrans with three contiguous stereocenters

Article abstract of DOI:10.1021/ol100378t

Figure presented Dihydropyran derivatives readily undergo addition to N-acyl imines in the presence of chiral phosphoric acids. This addition process yields an attractive product that is capable of a tandem oxidative-cyclization via an epoxide intermediate.

Full text of DOI:10.1021/ol100378t

ORGANIC
LETTERS
2010
Vol. 12, No. 9
1960-1963
Chiral Phosphoric Acid Catalyzed
Addition of Dihydropyrans to N-Acyl
Imines: Stereocontrolled Access to
Enantioenriched Spirocyclic
Oxazoletetrahydropyrans with Three
Contiguous Stereocenters
Guilong Li,†,‡ Matthew J. Kaplan,† Lukasz Wojtas,§ and Jon C. Antilla*,†
Department of Chemistry, UniVersity of South Florida, 4202 East Fowler AVenue
CHE205A, Tampa, Florida 33620, School of Chemistry and Chemical Engineering,
Sun Yat-Sen UniVersity, Guangzhou 510275, China, and Department of Chemistry
X-ray Facility, UniVersity of South Florida, Tampa, Florida 33620
jantilla@cas.usf.edu
Received February 15, 2010
ABSTRACT
Dihydropyran derivatives readily undergo addition to N-acyl imines in the presence of chiral phosphoric acids. This addition process yields
an attractive product that is capable of a tandem oxidative-cyclization via an epoxide intermediate.
Chiral Brønsted acids have been shown as highly effective
catalysts for stereocontrolled additions to imines.1 The use
of N-acyl imines, in particular, has been very successful for
activation by chiral phosphoric acid (PA)-based catalysis.2
As part of our ongoing efforts in the chiral PA activation of
N-acyl electrophiles,3 we have been continually interested
in establishing new stereocontrolled C-C bond forming
reactions. During the course of our investigation into the use
of dihydropyran (DHP) as a substrate for aza-Diels-Alder4
chemistry, a report by Mead and co-workers5 described the
achiral Mannich-type addition of DHP and derivatives to
N-acyl imines catalyzed by trifluoroacetic acid or BF3-OEt2.
Concurrent with the Mead study, we observed that the chiral
PA-catalyzed reaction of DHP with N-acyl imine 1 also
provided the direct Mannich product, rather than the [4 +
2] adduct (Scheme 1). We were excited because the addition,
if rendered highly enantioselective, would have the following
unique features: (a) it is a relatively novel carbon-carbon
bond forming reaction, which could provide synthetically
useful chiral allyl amines (or amides); (b) functionalized
chiral dihydropyran derivatives are found in numerous
bioactive natural products and compounds with medicinal
interest.6 We report herein, to the best of our knowledge,
† Department of Chemistry, University of South Florida.
‡ Sun Yat-Sen University.
§ Department of Chemistry X-ray Facility, University of South Florida.
(1) For reviews, see: (a) Akiyama, T. Chem. ReV. 2007, 107, 5744. (b)
Doyle, A. G.; Jacobsen, E. N. Chem. ReV. 2007, 107, 5713. (c) Terada, M.
Chem. Commun. 2008, 4097.
10.1021/ol100378t  2010 American Chemical Society
Published on Web 04/02/2010

afforded a lower yield of the major product, due in part to
the formation of more side products, while providing only
modest ee. We then turned our attention to the effect of
different substituents on the phenyl ring of the benzoyl group.
As shown in Table 1, introduction of a methoxy or methyl
group in the ortho or meta positions of the phenyl ring did
not induce a positive effect (entries 11 and 12). However,
to our delight, the same substituent groups in the para
position gave significant improvement on yield and ee
(entries 13 and 14; 83 and 85% ee, respectively). In addition,
the catalyst loading could be decreased to 2 mol %, providing
an even higher yield (98%) without compromising the
enantioselectivity (entry 15). Furthermore, a N,N-dimethy-
lamino-substituted N-acyl imine substrate provided the
highest enantioselectivity, up to 89% (entry 17), presumably
due to increased steric hindrance at the para position. The
N,N-dimethylamino-substituted N-acyl group has been re-
moved, as demonstrated by Terada et al.8
Once the optimized conditions were established, the
substrate scope of the asymmetric addition of DHP to N-acyl
imine derivatives was studied. This reaction is tolerant of a
variety of N-acyl imines (1a-1h). For example, the addition
of imines bearing electron-withdrawing groups (p-chloro, 1b,
entry 2; p-bromo, 1c, entry 3) gave very high yield and
excellent enantioselectivity, up to 90%. An example of an
N-acyl imine with an electron-donating group, such as para-
methyl, also allowed for a good yield and 90% ee (entry 5).
However, a strong electron-donating substituent had a
negative effect on the ee (78% ee, entry 6). Additionally,
the imines with methoxy (76% ee, entry 6) and fluoro (91%
ee, entry 7) substituents on the meta position provided similar
results in comparison to their para counterparts. We were
pleased to find the reaction general for various DHP
derivatives.
Scheme 1
.
DHP Addition to Imine Resulting in a
Mannich-Type Product
the first catalytic asymmetric addition of DHP derivatives
to N-acyl imines, together with interesting examples of the
potential synthetic utilization of this reaction.
We initiated our studies with VAPOL phosphoric acid3a
(5 mol % catalyst loading) as the catalyst and toluene as the
solvent. The reaction was run at room temperature and
yielded the addition product in 45% yield and 37% ee. This
result encouraged us to further explore the reaction condi-
tions. Catalyst screening showed that (R)-TRIP-PA7 gave
the best result in terms of enantioselectivity and yield.
Therefore, (R)-TRIP-PA was used to evaluate the effect of
solvent on the reaction. As shown in Table 1, coordinating
Table 1. Optimization of Reaction Conditions
As shown in Table 2, the reaction of DHP derivative 2b,
bearing an n-propyl group, afforded up to 92% yield and
PA, temp, time, yield,
b
entrya
R
solvent mol % °C
h
%
ee, %c
(2) (a) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356.
(b) Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2004, 126,
11804. (c) Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2005,
127, 9360. (d) Rueping, M.; Sugiono, E.; Theissmann, T.; Kuenkel, A.;
Kockritz, A.; Davtyan, A. P.; Nemati, N.; Beller, M. Org. Lett. 2007, 9,
1065. (e) Zeng, X.; Zeng, X.; Xu, Z.; Lu, M.; Zhong, G. Org. Lett. 2009,
11, 3036.
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
toluene
DCM
5
5
5
5
5
5
5
5
5
5
5
5
5
5
2
1
2
rt
rt
rt
rt
rt
rt
rt
rt
-20
50
rt
rt
rt
rt
rt
rt
rt
20
20
20
20
20
20
20
24
48
18
26
21
21
21
24
24
24
61
64
nd
24
nd
48
79
85
<10
31
80
73
90
82
98
78
76
64
33
na
54
na
28
60
71
40
64
72
72
83
85
85
81
89
2
3
THF
4
EtOAc
ether
DCE
hexane
CHCl3
CHCl3
CHCl3
5
6
(3) (a) Rowland, G. B.; Zhang, H.; Rowland, E. B.; Chennamadhavuni,
S.; Wang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2005, 127, 15696. (b) Liang,
Y.; Rowland, E. B.; Rowland, G. B.; Perman, J. A.; Antilla, J. C. Chem.
Commun. 2007, 4477. (c) Rowland, E. B.; Rowland, G. B.; Liang, Y.;
Perman, J. A.; Antilla, J. C. Org. Lett. 2007, 9, 2609. (d) Li, G.; Rowland,
E. B.; Rowland, G. B.; Antilla, J. C. Org. Lett. 2007, 9, 4065. (e) Rowland,
E. B.; Rowland, G. B.; Rivera-Otero, E.; Antilla, J. C. J. Am. Chem. Soc.
2007, 129, 12084. (f) Li, G.; Fronczek, F. R.; Antilla, J. C. J. Am. Chem.
Soc. 2008, 130, 12216.
7
8
9
10
11
12
13
14
15
16
17
3,5-MeOC6H3 CHCl3
2-MeC6H4
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
(4) (a) Gizecki, P.; Dhal, R.; Toupet, L.; Dujardin, G. Org. Lett. 2000,
2, 585. (b) Akiyama, T.; Morita, H.; Fuchibe, K. J. Am. Chem. Soc. 2006,
128, 13070. (c) Liu, H.; Cun, L. F.; Mi, A. Q.; Jiang, Y. Z.; Gong, L. Z.
Org. Lett. 2006, 8, 6023. Rueping, M.; Azap, C. Angew. Chem., Int. Ed.
2006, 45, 7832. (d) Liu, H.; Dagousset, G.; Masson, G.; Retailleau, P.;
Zhu, J. J. Am. Chem. Soc. 2009, 131, 4598.
4-Me2NC6H4 CHCl3
a Molar ratio of 1/2 ) 1.0/1.0 equiv. b With 4 Å MS added in entries
8 and 11-17. c Isolated yields. d Enantiomeric excess determined by chiral
HPLC.
(5) Cakir, S. P.; Mead, K. T. Synthesis 2008, 871.
(6) (a) Faulkner, D. J. Nat. Prod. Rep. 1998, 15, 113. (b) Clarke, P. A.;
Santos, S. Eur. J. Org. Chem. 2006, 2045. (c) Franke, P. T.; Richter, B.;
Jørgensen, K. A. Chem.sEur. J. 2008, 14, 6317.
solvents such as THF and ether (entries 3 and 5) gave poor
results. Chloroform provided the best yield at 85% and 71%
ee (entry 8).
Decreasing the temperature lowered the yield and ee
dramatically (entry 9). Increasing the temperature to 50 °C
(7) TRIP-PA was first prepared and used by List et al. See: Hoffmann,
S.; Seayad, A.; List, B. Angew. Chem., Int. Ed. 2005, 44, 7424.
(8) It has been shown that the N,N-dimethylamino N-acyl protecting
group can be removed in a two-step reaction sequence. Please see: Uraguchi,
D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2005, 127, 9360.
Org. Lett., Vol. 12, No. 9, 2010
1961

Table 2. Substrate Scope
entrya
R1 (1)
Ph (1a)
p-ClC6H4 (1b)
p-BrC6H4 (1c)
p-FC6H4 (1d)
p-CH3C6H4 (1e)
p-CH3OC6H4 (1f)
m-CH3OC6H4 (1g)
m-FC6H4 (1h)
p-ClC6H4 (1b)
p-ClC6H4 (1b)
p-ClC6H4 (1b)
p-ClC6H4 (1b)
p-ClC6H4 (1b)
R2 (2)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
time, h
product (3)
yield, %b
ee, %c
1d
2
3
4
5
6
7
8
9
10
11
12
13
21
24
39
25
21
25
20
24
15
18
23
19
25
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3bb
3bc
3bd
3be
3bf
76
90
94
88
80
79
95
86
92
72
92
92
95
89
90
90(S)e
89
90
78
76
91
92
90
89
88
H (2a)
n-Pr (2b)
i-butyl (2c)
i-pentyl(2d)
n-C6H13 (2e)
(CH2)2OCH3 (2f)
81
a Molar ratio of 1/2 ) 1.5/1.0 equiv. b Isolated yield. c Enantiomeric excess determined by chiral HPLC. d 1/2 ) 1.0/1.0 equiv. e Absolute configuration
was determined from X-ray diffraction of compound 4ca.
92% ee. The DHP derivatives with larger steric hindrance
and longer alkyl chain groups, such as reactants 2c and 2d,
also gave high enantioselectivities (90 and 89%, entries 10
and 11, respectively). Finally, the DHP derivative with
methoxyethyl substitution produced a lower ee (81%, entry
13), presumably due to the possible coordination of the ether
to the phosphoric acid catalyst.
polycyclic tetrahydropyran. As shown in Scheme 2, treating
chiral compound 3ba with an excess of m-CPBA, followed
by aqueous NaHSO3, afforded the spirocyclic oxazoletet-
rahydropyran 4ba in 84% yield and 90% ee.10 Under similar
reaction conditions, both 3ca and 3ea also provided the
corresponding spirocyclic compounds 4ca and 4ea with 92
and 90% ee, respectively. It is noteworthy that the overall
reaction sequence generates three chiral centers, including
one quaternary chiral center. The absolute configuration of
the spirocyclic oxazoletetrahydropyran was revealed to be
(S)-C10, (R)-C11, and (S)-C12 by single-crystal X-ray
diffraction of compound 4ca (Figure 1).
Scheme 2
.
Highly Selective Preparation of Chiral Spirocyclic
Oxazoletetrahydropyrans
Direct access to chiral spirocyclic compounds with a
quaternary stereogenic center represents a significant chal-
lenge in organic synthesis.9 The carbon-carbon double bond
of the functionalized chiral 3 provides a useful handle for
further synthetic transformations. We envisioned that ep-
oxidation of the double bond, followed by a tandem in situ
intramolecular ring opening, could occur to form a chiral
Figure 1. ORTEP representation of the X-ray structure of 4ca with
displacement ellipsoids shown at a 50% probability level.
The exact mechanism for this tandem reaction sequence
has not been precisely determined; however, it is reasonable
that the high stereoselectivity is induced by the vicinal chiral
(9) (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998,
37, 389. (b) Pradhan, R.; Patra, M.; Behera, A. K.; Mishra, B. K.; Behera,
R. K. Tetrahedron 2006, 62, 779. (c) Kotha, S.; Deb, A. C.; Lahiri, K.;
Manivannan, E. Synthesis 2009, 165.
(10) Gleave, D. M.; Savall, B. M.; McWhorter, W. W. Synth. Commun.
1997, 27, 2425.
1962
Org. Lett., Vol. 12, No. 9, 2010

reaction has been shown to provide potentially useful chiral
DHP derivatives in high yields and enantioselectivities. By
using the chiral DHP addition products as the starting
material, structurally unique spirocyclic oxazoletetrahydro-
pyrans could be synthesized stereoselectively via a tandem
epoxidation/ring-opening reaction sequence.
Acknowledgment. We thank the National Institutes of
Health (NIH GM-082935) and the National Science Founda-
tion (NSF-0847108) for financial support. We also thank Dr.
Wenhua Zheng (USF) for the preparation of TRIP-PA.
Figure 2. Plausible mechanism for the tandem cyclization leading
to the spirocyclic skeleton.
Note Added after ASAP Publication. The author name
Guilong was misspelled in the version of this paper published
on April 2, 2010; it was corrected in the version posted on
April 6, 2010.
amide group via hydrogen bonding interactions with m-
CPBA through a six-membered ring transition state I (Figure
2). Directed by the amide, m-CPBA reacts with the enol ether
from the Re face to stereoselectively form the epoxide. This
is followed by an intramolecular SN2 reaction (II) to provide
the chiral spirocyclic tetrahydropyran 4.
Supporting Information Available: Experimental pro-
cedures, characterization, and spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
In conclusion, we have reported the first catalytic asym-
metric addition of DHP derivatives to N-acyl imines. This
OL100378T
Org. Lett., Vol. 12, No. 9, 2010
1963