Pd-catalyzed asymmetric allylic amination of Morita-Baylis-Hillman adduct derivatives using chiral diaminophosphine oxides: DIAPHOXs

Article abstract of DOI:10.1021/ol0700207

(Chemical Equation Presented) Asymmetric allylic animation of allylic carbonates prepared from racemic Morita-Baylis-Hillman adducts proceeded in the presence of Pd catalyst, chiral diaminophosphine oxide (DIAPHOX), and BSA, affording the corresponding chiral aza-Morita-Baylis-Hillman adduct derivatives in excellent yield with up to 99% ee. The cyclic reaction products could be converted into various synthetically useful compounds such as chiral cyclic β-amino acids.

Full text of DOI:10.1021/ol0700207

ORGANIC
LETTERS
2007
Vol. 9, No. 5
927-930
Pd-Catalyzed Asymmetric Allylic
Amination of Morita Baylis Hillman
−
−
Adduct Derivatives Using Chiral
Diaminophosphine Oxides: DIAPHOXs
Tetsuhiro Nemoto, Takashi Fukuyama, Eri Yamamoto, Shinji Tamura,
Tomoaki Fukuda, Takayoshi Matsumoto, Yuichi Akimoto, and
Yasumasa Hamada*
Graduate School of Pharmaceutical Sciences, Chiba UniVersity, 1-33 Yayoi-cho,
Inage-ku, Chiba 263-8522, Japan
hamada@p.chiba-u.ac.jp
Received January 4, 2007
ABSTRACT
Asymmetric allylic amination of allylic carbonates prepared from racemic Morita
catalyst, chiral diaminophosphine oxide (DIAPHOX), and BSA, affording the corresponding chiral aza-Morita
in excellent yield with up to 99% ee. The cyclic reaction products could be converted into various synthetically useful compounds such as
chiral cyclic -amino acids.
−Baylis−Hillman adducts proceeded in the presence of Pd
−
Baylis Hillman adduct derivatives
−
â
Considerable efforts have been devoted to designing asym-
metric catalysts for the Morita-Baylis-Hillman reaction,
due to the versatile property of chiral Morita-Baylis-
Hillman adducts.1 The Trost group, on the other hand,
developed an alternative strategy to synthesize chiral Morita-
Baylis-Hillman adducts based on a conceptually distinct
strategy: deracemization of racemic Morita-Baylis-Hill-
man adduct derivatives using Pd-catalyzed asymmetric allylic
substitution.2,3 Various oxygen nucleophiles are competent
for this deracemization process, and several enantioselective
total syntheses of natural products have been achieved using
the present strategy.2b-e In contrast, there are limited ap-
plications of nitrogen nucleophiles to this deracemization
process.4 This type of transformation provides easy access
to various chiral aza-Morita-Baylis-Hillman adduct deriva-
tives. An efficient method to prepare this versatile class of
compounds can be a useful tool in asymmetric synthesis of
nitrogen-containing natural products. We describe herein a
general and highly enantioselective allylic amination of
Morita-Baylis-Hillman adduct derivatives using Pd-chiral
diaminophosphine oxide catalyst systems.
(1) For a review, see: Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem.
ReV. 2003, 103, 811.
(2) (a) Trost, B. M.; Tsui, H.-C.; Toste, F. D. J. Am. Chem. Soc. 2000,
122, 3534. (b) Trost, B. M.; Thiel, O. R.; Tsui, H.-C. J. Am. Chem. Soc.
2002, 124, 11616. (c) Trost, B. M.; Thiel, O. R.; Tsui, H.-C. J. Am. Chem.
Soc. 2003, 125, 13155. (d) Trost, B. M.; Machacek, M. R.; Tsui, H.-C. J.
Am. Chem. Soc. 2005, 127, 7014. (e) Trost, B. M.; Tang, W.; Toste, F. D.
J. Am. Chem. Soc. 2005, 127, 14785.
We recently reported that aspartic acid-derived P-chiro-
genic diaminophosphine oxides (DIAPHOXs) 1 (Figure 1)
(4) (a) Trost, B. M.; Oslob, J. D. J. Am. Chem. Soc. 1999, 121, 3057.
(b) Mori, M.; Nakanishi, D.; Kajishima, D.; Sato, Y. J. Am. Chem. Soc.
2003, 125, 9801.
(3) For a review on the Pd-catalyzed asymmetric allylic substitution
reaction, see: Trost, B. M.; Crawley, M. L. Chem. ReV. 2003, 103, 2921.
10.1021/ol0700207 CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/07/2007

Table 1. Optimization of the Reaction Conditions
entry
DIAPHOX
T (°C)
yieldb (%)
eec (% ee)
1d
2d
3d
4d
5d
6d
7d
8e
1a
1b
1c
1d
1e
1f
1g
1f
1f
4
4
4
4
4
4
4
4
91
92
97
99
96
99
99
99
99
87
69
83
71
90
94
89
94
99
Figure 1. (S,RP)-DIAPHOXs.
are useful chiral ligands for Pd-catalyzed asymmetric allylic
substitution reactions.5-7 We first selected asymmetric allylic
amination of 2-methoxycarbonyl 2-cyclohexenyl alcohol
derivatives with benzylamine 3a as the model reaction
because the cyclic products such as 4aa are not readily
accessible using the asymmetric aza-Morita-Baylis-Hill-
man reaction (Table 1).8 Although cyclic adduct 4aa with
low enantiomeric excess was obtained when an acetate
derivative (26% ee) and a pentafluorobenzoate derivative
(31% ee) were used as substrates, allylic amination of
carbonate derivative 2a proceeded in the presence of 5 mol
% of Pd catalyst and 10 mol % of (S,RP)-1a at 4 °C, affording
(S)-4aa in 91% yield and 87% ee. The effect of the ligand
structure revealed that the introduction of electron-donating
groups onto the aromatic rings attached to the nitrogen atoms
increases the enantioselectivity, and the 3,4-dimethoxy-type
ligand (S,RP)-1f was best for asymmetric induction. More-
over, enantioselectivity was increased when the reaction was
performed at a lower temperature. Using 2 mol % of Pd
catalyst and 4 mol % of (S,RP)-1f, cyclic product (S)-4aa
was obtained in 99% yield with 99% ee (entry 9).9
9e
-30
a [η3-C3H5PdCl]2 (1 or 2.5 mol %) was used. b Isolated yield. c Deter-
mined by HPLC analysis. d 5 mol % of Pd catalyst and 10 mol % of
DIAPHOX were used. e 2 mol % of Pd catalyst and 4 mol % of DIAPHOX
were used.
Having developed efficient conditions, we next examined
the scope and limitation of different substrates (Table 2).10
When 2 mol % of Pd catalyst and 4 mol % of (S,RP)-1f were
used, asymmetric allylic amination of 2a using primary
amines (entries 1-7), a secondary amine (entry 8), and an
aromatic amine11 (entry 9) proceeded efficiently to provide
the corresponding products in excellent yield and enantio-
meric excess. It is noteworthy that the present catalysis could
be performed on a gram scale using 1 mol % of the catalyst,
and (S)-4aa was obtained in excellent yield without any
decrease in the enantiomeric excess (entry 2).10 Other cyclic
substrates with a five-membered ring and a seven-membered
ring were also applicable to this reaction, affording the
corresponding chiral allylic amines in 91% ee and 84% ee,
respectively (entries 10 and 11). Furthermore, asymmetric
allylic amination of cyclic substrates with other electron-
withdrawing groups was examined using benzylamine as the
nucleophile (entries 12-15). A substrate with a simple
secondary amide, as well as the Weinreb amide-type
substrate, could be utilized for this reaction system, giving
the corresponding products in excellent yield and enantio-
meric excess. Similarly, a reaction using a cyclic substrate
with a nitrile group proceeded at -40 °C to provide the
corresponding product in high enantiomeric excess. In
addition, linear substrates with a nitrile group were examined
(entries 15 and 16). Asymmetric allylic amination of 1,3-
diphenylallyl carbonate derivative 2g proceeded at 4 °C to
provide the corresponding product in 89% ee.12 Monosub-
stituted-type substrates such as 2h are applicable to the
Trost’s catalyst system, giving branched products with high
regio and enantioselectivity.2a-d In our catalyst system,
(5) (a) Nemoto, T.; Matsumoto, T.; Masuda, T.; Hitomi, T.; Hatano, K.;
Hamada, Y. J. Am. Chem. Soc. 2004, 126, 3690. (b) Nemoto, T.; Masuda,
T.; Matsumoto, T.; Hamada, Y. J. Org. Chem. 2005, 70, 7172. (c) Nemoto,
T.; Fukuda, T.; Matsumoto, T.; Hitomi, T.; Hamada, Y. AdV. Synth. Catal.
2005, 347, 1504. (d) Nemoto, T.; Masuda, T.; Akimoto, Y.; Fukuyama, T.;
Hamada, Y. Org. Lett. 2005, 7, 4447. (e) Nemoto, T.; Jin, L.; Nakamura,
H.; Hamada, Y. Tetrahedron Lett. 2006, 47, 6577. (f) Nemoto, T.; Sakamoto,
T.; Matsumoto, T.; Hamada, Y. Tetrahedron Lett. 2006, 47, 8737.
(6) For other examples of transition metal catalysis using diaminophos-
phine oxides, see: (a) Ackermann, L.; Born, R. Angew. Chem., Int. Ed.
2005, 44, 2444. (b) Ackermann, L.; Born, R.; Spatz, J. H.; Meyer, D. Angew.
Chem., Int. Ed. 2005, 44, 7216. (c) Ackermann, L.; Althammer, A.; Born,
R. Angew. Chem., Int. Ed. 2006, 45, 2619. (d) For a review, see:
Ackermann, L. Synthesis 2006, 1557.
(7) For other examples of transition metal-catalyzed asymmetric reactions
using chiral phosphine oxides, see: (a) Jiang, X.-B.; Minnaard, A. J.; Hessen,
B.; Feringa, B. L.; Duchateau, A. L. L.; Andrien, J. G. O.; Boogers, J. A.
F.; de Vries, J. G. Org. Lett. 2003, 5, 1503. (b) Dai, W.-M.; Yeung, K. K.
Y.; Leung, W. H.; Haynes, R. K. Tetrahedron: Asymmetry 2003, 14, 2821.
(c) Bigeault, J.; Giordano, L.; Buono, G. Angew. Chem., Int. Ed. 2005, 44,
4753.
(8) As far as we know, there are no reports of an intramolecular
asymmetric aza-Morita-Baylis-Hillman reaction. For intermolecular cata-
lytic asymmetric aza-Morita-Baylis-Hillman reactions, see: (a) Shi, M.;
Xu, Y.-M. Angew. Chem., Int. Ed. 2002, 41, 4507. (b) Shi, M.; Chen, L.-
H. Chem. Commun. 2003, 1310. (c) Kawahara, S.; Nakano, A.; Esumi, T.;
Iwabuchi, Y.; Hatakeyama, S. Org. Lett. 2003, 5, 3103. (d) Balan, D.;
Adolfsson, H. Tetrahedron Lett. 2003, 44, 2521. (e) Raheen, I. T.; Jacobsen,
E. N. AdV. Synth. Catal. 2005, 347, 1701. (f) Matsui, K.; Takizawa, S.;
Sasai, H. J. Am. Chem. Soc. 2005, 127, 3680. (g) See also: Krawczyk, E.;
Owsianik, K.; Skowronska, A. Tetrahedron 2005, 61, 1449.
(10) For the experimental procedure, see the Supporting Information.
(11) No reaction occurred when 4-methoxyphenol was used as a
nucleophile.
(9) Although this reaction was examined under several catalyst conditions
with representative chiral ligands, no satisfactory results were obtained. See
the Supporting Information for details.
(12) Although asymmetric allylic amination of a linear substrate with
an ester group proceeded under the same reaction conditions, the product
was obtained as the mixture of geometrical isomers of the olefin.
928
Org. Lett., Vol. 9, No. 5, 2007

Table 2. Substrate Scope
entry
substrate
R1R2NH
product
T (°C)
timea (h)
yieldb (%)
eec (% ee)
1
2d
3
4
5
6
7
8
9e
10e,f
11e
12
13e
14
15g
16
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
benzylamine (3a)
benzylamine (3a)
4-methoxybenzylamine (3b)
furfurylamine (3c)
allylamine (3d)
isopropylamine (3e)
Nin-Boc-tryptamine (3f)
morpholine (3g)
4-methoxyaniline (3h)
benzylamine (3a)
benzylamine (3a)
benzylamine (3a)
benzylamine (3a)
benzylamine (3a)
benzylamine (3a)
benzylamine (3a)
4aa
4aa
4ab
4ac
4ad
4ae
4af
4ag
4ah
4ba
4ca
4da
4ea
4fa
-30
-30
-30
-30
-40
-30
-30
-10
-30
-40
-40
-30
-30
-40
4
24
24
24
24
24
24
24
15
48
18
18
48
32
18
24
24
99
98
99
99
99
92
97
98
99
81
99
94
98
99
96
0 (99)h
99 (S)
99 (S)
97 (S)
98
98
99
96
99
94
91 (S)
84
98
99 (S)
95
2g
2h
4ga
4ha
89
4
a Reaction times have not been optimized. b Isolated yield. c Determined by HPLC analysis. For the determination of the absolute configuration, see the
Supporting Information. d 1 mol % of Pd catalyst and 2 mol % of (S,RP)-1f were used. Reaction scale: 1.07 g of 2a was used. e (S,RP)-1a was used as the
chiral ligand. Results for the use of other DIAPHOXs are summarized in the Supporting Information. f Dichloroethane was used as the solvent. g (S,RP)-1e
was used as the chiral ligand. Results for the use of other DIAPHOXs are summarized in the Supporting Information. h Yield of the linear product (geometry
of olefin: Z).
however, the corresponding linear product was obtained
exclusively.
trifluoroacetic acid, gave R,â-unsaturated ester 7 in 98% yield
without any noticeable loss of optical purity (97% ee).15 This
product could be transformed into the cyclic syn-â-amino
acid derivative 8 with good diastereoselectivity (syn/anti )
5:1).16 The usefulness of these compounds was further
Thus, the present deracemization reaction of allylic
carbonates prepared from racemic Morita-Baylis-Hillman
adducts through asymmetric allylic amination had broad
generality for both electrophiles and amine nucleophiles,
affording chiral allylic amines, so-called aza-Morita-Bay-
lis-Hillman adducts, in up to 99% ee. To demonstrate the
usefulness of these chiral allylic amines, several diastereo-
selective modifications were performed (Scheme 1).10 Chiral
cyclic â-amino acids have gained much attention due to their
increasing importance for the synthesis of â-peptides.13 There
are, however, few catalytic asymmetric synthetic methods.14
Our synthesis started with (S)-4aa and (S)-4ab. Both olefin
hydrogenation and debenzylation of (S)-4aa using Pd(OH)2-
C, followed by protection of the resulting free amine with a
carbobenzyloxy (Z) group, afforded the cyclic anti-â-amino
acid derivative (S,S)-5 in 88% yield as a nearly optically
pure compound (99% ee).15 In this hydrogenation, the
reaction proceeded with complete diastereoselection, giving
the anti product exclusively. On the other hand, protection
of (S)-4ab with a tosyl group, followed by treatment with
Scheme 1
(13) For a review, see: Cheng, R. P.; Gellman, S. H.; DeGrado, W. F.
Chem. ReV. 2001, 101, 3219.
(14) (a) Tang, W.; Wu, S.; Zhang, X. J. Am. Chem. Soc. 2003, 125,
9570. (b) Mita, T.; Fujimori, I.; Wada, R.; Wen, J.; Kanai, M.; Shibasaki,
M. J. Am. Chem. Soc. 2005, 127, 11252.
(15) Enantiomeric excess was determined by HPLC analysis.
Org. Lett., Vol. 9, No. 5, 2007
929

demonstrated. After the formation of lithium enolate of 5,
diastereoselective alkylation was performed using allyl
bromide as an electrophile,17 affording the product with an
all-carbon quaternary stereocenter in 73% yield with high
diastereoselectivity (dr ) 13:1).16 Weinreb amide-type adduct
(S)-4ea (99% ee) reacted with a Grignard reagent at -40
°C to provide the corresponding enone 9 in 99% yield (99%
ee).15,18 This enone could be converted into R,â-epoxy ketone
10 (82% yield) and 1,3-amino alcohol 11 (83% yield) in a
highly diastereoselective manner.16 Moreover, Diels-Alder
reaction of 4aa with the Danishefsky’s diene proceeded in
the presence of Et2AlCl, giving the bicyclic product 12 in
88% yield as a single diastereomer.16
In conclusion, we succeeded in the general and highly
enantioselective allylic amination of Morita-Baylis-Hillman
adduct derivatives using Pd-DIAPHOX catalyst systems. The
versatile property of the reaction products was demonstrated.
Application to asymmetric synthesis of nitrogen-containing
natural products is ongoing.
Acknowledgment. This work was supported in part by
a Grant-in Aid for Encouragement of Young Scientists (A)
from the Ministry of Education, Culture, Sports, Science,
and Technology, Japan, and the Banyu Award in Synthetic
Organic Chemistry, Japan.
1
(16) Diastereoselectivity was determined by H-NMR analysis. For the
Supporting Information Available: Experimental pro-
cedures and supplementary data, compound characterization,
and NMR charts. This material is available free of charge
via the Internet at http://pubs.acs.org.
epoxidation and the Diels-Alder reaction, no peaks corresponding to the
diastereomer could be detected. The relative configuration was determined
by the NOE experiment. See the Supporting Information for details.
(17) Seebach, D.; Estermann, H. Tetrahedron Lett. 1987, 28, 3103.
(18) Asymmetric allylic amination of cyclohexenyl carbonate with phenyl
ketone using benzylamine gave 9 with low enantiomeric excess (37% ee).
This was due to the competitive racemic pathway through a conjugate
addition of benzylamine. See the Supporting Information for details.
OL0700207
930
Org. Lett., Vol. 9, No. 5, 2007