Design of chiral N-triflyl phosphoramide as a strong chiral Bronsted acid and its application to asymmetric Diels-Alder reaction

Article abstract of DOI:10.1021/ja062508t

A highly reactive and acidic chiral Bronsted acid catalyst, chiral N-triflyl phosphoramide, was developed. Highly enantioselective Diels-Alder reaction of α,β-unsaturated ketone with silyloxydiene was demonstrated using this chiral Bronsted acid catalyst. Copyright

Full text of DOI:10.1021/ja062508t

Published on Web 07/06/2006
Design of Chiral N-Triflyl Phosphoramide as a Strong Chiral Brønsted Acid
and Its Application to Asymmetric Diels-Alder Reaction
Daisuke Nakashima and Hisashi Yamamoto*
Department of Chemistry, UniVersity of Chicago, 5735 South Ellis AVenue, Chicago, Illinois 60637
Received April 19, 2006; E-mail: yamamoto@uchicago.edu
Metal-free chiral Brønsted acid catalysis has recently emerged
as a new class of chiral organic catalysis. Several quite nice chiral
Brønsted acids, such as urea/thiourea, alcohol, and phosphoric acid,
have already been reported as a chiral electron acceptor of carbonyl
and imine compounds.1 However, compared with chiral metal Lewis
Figure 1. Enhancement of the acidity of Brønsted acid by a strong electron
acid catalysts, the utility of chiral Brønsted acid catalysts is still
limited to the reactive substrates. This drawback can be overcome
by designing a Brønsted acid catalyst with higher acidity. To
increase the acidity of Brønsted acids, it is necessary to increase
the stability of the counteranion. Koppel and co-workers reported
that introduction of a strong electron acceptor group, such as d
NTf, into an acid system instead of an dO group increased the
stability of counteranions and their acidity (Figure 1).2 For example,
the pKa of N-triflyl benzamide in acetonitrile (11.06) is much lower
than that of benzoic acid (20.7). Recently, Akiyama and Terada’s
chiral phosphoric acid was reported to be a most powerful chiral
Brønsted acid.3 Unfortunately, however, the relatively low acidity
of phosphoric acid makes this excellent catalyst of rather limited
use in future applications. We expected that strong chiral Brønsted
acid would be achieved by introduction of a dNTf group into the
phosphoric acid.4
acceptor.
Scheme 1. Preparation of Chiral Phosphoramide
Table 1. Reactivity for the Diels-Alder Reactionsa
Metal Lewis acid-catalyzed asymmetric Diels-Alder reaction
is one of the most studied reactions. However, chiral metal Lewis
acid-catalyzed asymmetric Diels-Alder reaction of R,â-unsaturated
ketone is still rare because the recognition of two lone pairs and
the control of the s-cis/s-trans conformation of R,â-unsaturated
ketone are difficult.5,6 Recently, we reported that Brønsted acid is
a suitable catalyst for the Diels-Alder reaction of R,â-unsaturated
ketone.7 Herein we describe the preparation of a new designer chiral
strong Brønsted acid and its application to the asymmetric Diels-
Alder reaction of R,â-unsaturated ketone.8
diene
(equiv)
chiral
Brønsted acid
time
(h)
yield
(%)
eeb (%)
(config.)
en try
solvent
1
2
3
4
5
6
4
(1.2)
1
2
3
1
2
3
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
toluene
2
2
1
3
3
3
0
91
86
n.d.
9 (S)
32 (R)
n.d.
n.d.
92
5c
(1.5)
0
As shown in Scheme 1, chiral N-triflyl phosphoramides 2 and 3
were easily synthesized from optically active BINOL derivatives
by phosphorylation with POCl3 and amidation between resultant
phosphoryl chloride and TfNH2.
<10
95d
a Only endo product was observed by H NMR. b Enantiomeric excess
was determined by GC analysis. c (Z,E):(E,E) ) 86:14. d Mixture of olefin
regio isomer; see Table 2.
1
First, to compare the catalytic activity of chiral Brønsted acids
1-3, the asymmetric Diels-Alder reactions of ethyl vinyl ketone
were investigated; the results are summarized in Table 1. Although,
using 5 mol % of 1 with 4, no reaction was observed (entry 1 in
Table 1), 2 and 3 gave desired Diels-Alder product in high yield
with moderate enantiomeric excess (entries 2 and 3 in Table 1).
Thus, the reactivity was enhanced dramatically by the introduction
of a dNTf group into the phosphoric acid. Even with the more
reactive 5, 1 showed no catalytic activity (entry 4 in Table 1).
However, whereas 2 gave a trace amount of Diels-Alder product,
3 provided the desired product in quantitative yield with high
enantiomeric excess (entries 5 and 6 in Table 1).9 This observed
significant difference of reactivity between 2 and 3 is explained
by the rapid quenching of catalyst with 5. In fact, the same reaction
using 5 mol % of 3, pretreated with TIPS enol ether of acetophen-
one, gave no desired product (Scheme 2);10 silylated 3 has no
Scheme 2. Denial of Chiral Silyl Lewis Acid
catalytic activity.11 In entry 5, 2 was initially silylated by 5 under
the reaction conditions, whereas, in entry 6, silylation of 3 might
be much slower than 2 because of the overwhelming bulkiness
adjacent to the acidic proton.
Next we optimized the reaction condition for the asymmetric
Diels-Alder reaction with 5. Basically aromatic solvent, such as
toluene, is suitable for this reaction. Ethylbenzene and chloroben-
zene gave almost the same results as toluene (entries 1-3 in Table
2). Using CH2Cl2 as a solvent, the yield was suddenly decreased
probably due to the dimerization of diene (entry 4 in Table 2). In
9
9626
J. AM. CHEM. SOC. 2006, 128, 9626-9627
10.1021/ja062508t CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Solvent Effect for Asymmetric Diels-Alder Reaction
catalyst. Further applications of N-triflyl phosphoramide to other
organic reactions are underway in our laboratory.
Acknowledgment. Financial support for this project has been
provided by SORST, Japan Science and Technology (JST), and
The University of Chicago.
yield
entry
solvent
(%)
A:Bb
ee (%)a
Supporting Information Available: Experimental procedure and
spectroscopic data of new compounds. This material is available free
of charge via Internet at http://pubs.acs.org.
1
2
3
toluene
95
83
95
76:24
78:22
71:29
92
93
93
ethylbenzene
chlorobenzene:
toluene ) 1:2
CH2Cl2
References
4
5
55
99
n.d.
85:15
81
80
hexane
(1) For reviews, see: (a) Schreiner, P. R. Chem. Soc. ReV. 2003, 32, 289. (b)
Seayad, J.; List, B. Org. Biomol. Chem. 2003, 3, 719. (c) Pihko, P. M.;
Angew. Chem., Int. Ed. 2004, 43, 2062. (d) Taylor, M. S.; Jacobsen, E.
N. Angew. Chem., Int. Ed. 2006, 45, 1520.
a Enantiomeric excess was determined by GC analysis after cleavage of
1
the TIPS group. b Ratio of A:B was determined by H NMR.
(2) (a) Burk, P.; Koppel, I. A.; Koppel, I.; Yagupolskii, L. M.; Taft, R. W. J.
Comput. Chem. 1996, 17, 30. (b) Leito, I.; Kaljurand, I.; Koppel, I. A.;
Yagupolskii, L. M.; Vlasov, V. M. J. Org. Chem. 1998, 63, 7868. (c)
Koppel, I. A.; Koppel, J.; Leito, I.; Koppel, I.; Mishima, M.; Yagupolskii,
L. M. J. Chem. Soc., Perkin Trans. 2 2001, 229. (d) Yagupolskii, L. M.;
Petrik, V. N.; Kondratenko, N. V.; Soova¨li, L.; Kaljurand, I.; Leito, I.;
Koppel, I. A. J. Chem. Soc., Perkin Trans. 2 2002, 1950.
Table 3. Substrate Scopea
(3) Chiral phosphoric acid: (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe,
K. Angew. Chem., Int. Ed. 2004, 43, 1566. (b) Uraguchi, D.; Terada, M.
J. Am. Chem. Soc. 2004, 126, 5356. (c) Uraguchi, D.; Sorimachi, K.;
Terada, M. J. Am. Chem. Soc. 2004, 126, 11804. (d) Uraguchi, D.;
Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2005, 127, 9360. (e)
Akiyama, T.; Saitoh, Y.; Morita, H.; Fuchibe, K. AdV. Synth. Catal. 2005,
347, 1523. (f) Akiyama, T.; Morita, H.; Itoh, J.; Fuchibe, K. Org. Lett.
2005, 7, 2583. (g) Rowland, G. B.; Zhang, H.; Rowland, E. B.;
Chennamadhavuni, S.; Wang, Y.; Antilla, J. J. Am. Chem. Soc. 2005,
127, 15696. (h) Rueping, M.; Sugiono, E.; Azap, C.; Theissmann, T.;
Bolte, M. Org. Lett. 2005, 7, 3781. (i) Hoffman, S.; Seayad, A. M.; List,
B. Angew. Chem., Int. Ed. 2005, 44, 7424. (j) Terada, M.; Sorimachi, K.;
Uraguchi, D. Synlett 2006, 133. (k) Akiyama, T.; Tamura, Y.; Itoh, J.;
Morita, H.; Fuchibe, K. Synlett 2006, 141. (l) Storer, R. I.; Carrera, D.
E.; Ni, Y.; Macmillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 84. (m)
Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128, 1086.
(n) Rueping, M.; Sugiono, E.; Azap, C. Angew. Chem., Int. Ed. 2006, 45,
2617. (o) Terada, M.; Machida, K.; Sorimachi, K. Angew. Chem., Int.
Ed. 2006, 45, 2254.
entry
R3Sib
R1
yield (%)
ee (%)c
1
TBS
Me
Me
H
43
95e
92
92
88
85
92
87
82
91
2d
3f
4
TIPS
TIPS
TIPS
TIPS
TIPS
TIPS
TIPS
43g
Bn
>99
>99
>99
35
5
6
7
8
(4-TBSOC6H4)CH2
(4-MOMOC6H4)CH2
(4-HOC6H4)CH2
BzOCH2CH2
>99
a (Z,E)-Silyloxydiene is major. b TBS ) tert-butyldimethylsilyl, TIPS )
triisopropylsilyl. c Enantiomeric excess was determined by GC analysis after
cleavage of silicon or by HPLC analysis directly (see Supporting Informa-
tion). d Reaction time was 3 h. e 76:24 mixture of olefin regio isomer. f 3
(15 mol %) and ethyl vinyl ketone (3 equiv) were used. g Yield was
determined after the cleavage of the TIPS group because the compound is
almost a 1:1 mixture of olefin regio isomer.
(4) The second and third pKa values of N-triflyl phosphoramide ((HO)2P(O)-
NHTf) are about 4 and 5 pKa units lower than that of H3PO4 (7.21 and
12.31, respectively): Burlingham, B. T.; Widlanski, T. S. J. Org. Chem.
2001, 66, 7561.
(5) Asymmetric Diels-Alder reaction of ketone: (a) Ryu, D. H.; Lee, T.
W.; Corey, E. J. J. Am. Chem. Soc. 2002, 124, 9992. (b) Ryu, D. H.;
Corey, E. J. J. Am. Chem. Soc. 2003, 125, 6388. (c) Hawkins, J. M.;
Nambu, M.; Loren, S. Org. Lett. 2003, 5, 4293. (d) Hu, Q.-Y.; Zhou, G.;
Corey, E. J. J. Am. Chem. Soc. 2004, 126, 13708. (e) Ryu, D. H.; Zhou,
G.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 4800. (f) Futatsugi, K.;
Yamamoto, H. Angew. Chem., Int. Ed. 2005, 44, 1484. (g) Singh, R. S.;
Harada, T. Eur. J. Org. Chem. 2005, 3433.
the nonpolar solvent, such as hexane, the reaction still proceeded
cleanly, but the enantiomeric excess was slightly decreased (entry
5 in Table 2).
The substrate scope of the asymmetric Diels-Alder reactions
between ethyl vinyl ketone and silyloxydienes is summarized in
Table 3. The bulkiness of the silyl group did not affect the
enantioselectivity. The yields of reactions are, however, quite
sensitive to the stability of silyloxydienes due to the protonation
of diene and deactivation (silylation) of catalyst (entries 1 and 2 in
Table 3).12 For the same reason, R-nonsubstituent silyloxydiene gave
relatively low yield but still maintained the high enantiomeric excess
value (entry 3 in Table 3). Interestingly, the olefin migration was
not observed under the reaction conditions when tert-butyldimeth-
ylsilyloxydiene was used or when R1 was a sterically hindered
group, such as a benzyl (entries 1 and 4-8 in Table 3). The acid-
sensitive groups, such as a silyl ether and methoxymethyl ether,
are tolerant in this reaction (entries 5 and 6 in Table 3). Usually,
the free hydroxyl group is not compatible with the chiral metal
Lewis acid catalyst; however, it is noteworthy that the reaction
tolerates this group with chiral Brønsted acid catalyst (entry 7 in
Table 3). The Lewis basic functional group, ester moiety, did not
affect either the reactivity or the enantioselectivity (entry 8 in Table
3).
(6) Another approach for the asymmetric Diels-Alder reaction of ketone:
Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124,
2458.
(7) Nakashima, D.; Yamamoto, H. Org. Lett. 2005, 7, 1251.
(8) Asymmetric Diels-Alder reaction catalyzed by chiral Brønsted acid: (a)
Schuster, T.; Bauch, M.; Du¨lrner, G.; Go¨bel, M. W. Org. Lett. 2000, 2,
179. (b) Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature
2003, 424, 146. (c) Thadani, A. N.; Stankovic, A. R.; Rawal, V. H. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5846. (d) Du, H.; Zhao, D.; Ding, K.
Chem.sEur. J. 2004, 10, 5964. (e) Tonoi, T.; Mikami, K. Tetrahedron
Lett. 2005, 46, 6355. (f) Zhuang, W.; Poulsen, T. B.; Jørgensen, K. A.
Org. Biomol. Chem. 2005, 3, 3284. (g) Unni, A. K.; Takenaka, N.;
Yamamoto, H.; Rawal, V. H. J. Am. Chem. Soc. 2005, 127, 1336. (h)
Rajaram, S.; Sigman, M. S. Org. Lett. 2005, 7, 5473. (i) Zhang, X.; Du,
H.; Wang, Z.; Wu, Y.-D.; Ding, K. J. Org. Chem. 2006, 71, 2862.
(9) When methyl vinyl ketone was used instead of ethyl vinyl ketone,
enantioselectivity decreased to 48% ee.
(10) When TIPS enol ether of acetophenone and 3 were mixed in CD2Cl2,
both the peak shift of 3 and the generation of acetophenone were observed
by 1H NMR.
(11) Our contribution to the silyl cation chemistry: (a) Ishihara, K.; Hiraiwa,
Y.; Yamamoto, H. Synlett 2001, 1851. (b) Ishihara, K.; Hiraiwa, Y.;
Yamamoto, H. Chem. Commun. 2002, 1564. (c) Hasegawa, A.; Ishihara,
K.; Yamamoto, H. Angew. Chem., Int. Ed. 2003, 42, 5731. (d) Boxer, M.
B.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 48.
In conclusion, we have developed a highly reactive and acidic
chiral Brønsted acid catalyst, chiral N-triflyl phosphoramide. Highly
enantioselective Diels-Alder reaction of R,â-unsaturated ketone
with silyloxydiene was demonstrated using this chiral Brønsted acid
(12) TBS enol ether is more reactive than TIPS enol ether: Mayr, H.; Kempf,
B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66.
JA062508T
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