A convenient synthesis and the asymmetric hydrogenation of N-phthaloyl dehydroamino acid esters

Article abstract of DOI:10.1021/ol800996j

(Chemical Equation Presented) A convenient synthetic method was reported for the preparation of N-phthaloyl dehydroamino acid esters from easily accessible vinyl bromides (or vinyl tosylate) and potassium phthalimide. Rh-catalyzed asymmetric hydrogenation

Full text of DOI:10.1021/ol800996j

ORGANIC
LETTERS
2008
Vol. 10, No. 14
3033-3036
A Convenient Synthesis and the
Asymmetric Hydrogenation of
N-Phthaloyl Dehydroamino Acid Esters
Jian Chen,†,‡ Qiang Liu,† Weicheng Zhang,‡ Stephen Spinella,‡ Aiwen Lei,*,† and
Xumu Zhang*,†,‡
College of Chemistry and Molecular Sciences, Wuhan UniVersity, P.R. China, and
Department of Chemistry and Chemical Biology and Department of Pharmaceutical
Chemistry, Rutgers UniVersity, The State UniVersity of New Jersey, Piscataway,
New Jersey 08854
aiwenlei@whu.edu.cn; xumu@rci.rutgers.edu
Received April 30, 2008
ABSTRACT
A convenient synthetic method was reported for the preparation of N-phthaloyl dehydroamino acid esters from easily accessible vinyl bromides
(or vinyl tosylate) and potassium phthalimide. Rh-catalyzed asymmetric hydrogenation of these substrates with TangPhos gave the products
with good to excellent enantioselectivities (up to 99% ee).
In transition metal mediated asymmetric hydrogenation1 of
functionalized substrates, a secondary chelating group near
the unsaturated double bond is important to achieve high
reactivity as well as excellent enantioselectivity. For example,
both dehydroamino acids and enamides possess an amide
moiety, which not only masks the amine but also participates
in chelation with metal during hydrogenation reactions. So
far the most applied N-protecting groups are acyl groups,
such as acetyl and benzyol. After hydrogenation, these groups
can be removed under carefully controlled condition to afford
the free amino group for further transformations. In contrast,
other potentially useful protecting groups have received little
attention. A recent work by Feringa and co-workers dem-
onstrated the formyl group as an effective N-protecting group
for R-dehydroamino acids, and excellent ee’s were obtained
in the hydrogenation of these new substrates.2 Moreover,
the formyl group can be removed under milder conditions
than acetyl group. In our studies on new substrates for
asymmetric hydrogenation,3 we conceived phthalimide as a
valuable protecting group for primary amines, which can be
cleaved under mild conditions without racemization. A
number of interesting substrates containing such functionality
have been developed and subjected to hydrogenation with
† Wuhan University.
‡ Rutgers University.
(1) (a) Jacobsen, E. N.; Pfaltz, A.; Yamamoto,H. ComprehensiVe
Asymmetric Catalysis I-III; Springer: Berlin, New York, 1999. (b) Noyori,
R. Asymmetric Catalysis in Organic Synthesis; Wiley: New York, 1994.
(c) Ojima, I. Catalytic Asymmetric Synthesis, 2nd ed.; Wiley-VCH: New
York, 2000. (d) Tang, W.; Zhang, X. Chem. ReV. 2003, 103, 3029.
(2) Panella, L.; Aleixandre, A. M.; Kruidhof, G. J.; Robertus, J.; Feringa,
B. L.; de Vries, J. G.; Minnaard, A. J. J. Org. Chem. 2006, 71, 2026.
(3) Zhang, W.; Chi, Y.; Zhang, X. Acc. Chem. Res. 2007, 40, 1278.
10.1021/ol800996j CCC: $40.75
Published on Web 06/13/2008
2008 American Chemical Society

excellent enantioselectivities, including amino ketone 1 and
enamides 2 and 3 (Figure 1).4 Recently, others have also
Figure 1. Functional groups of phthalimido.
succeeded in asymmetric hydrogenation of phthalimide-
bearing olefins.5 To further expand this usage, we herein
report a novel synthesis of N-phthaloyl dehydroamino acid
esters 6 and 7 via the reaction of vinyl bromide 4 or vinyl
tosylates 9 with potassium phthalimide 5. To our knowledge,
so far there is only one report concerning the synthesis of
such phthalimide-bearing substrates.6 As a complementary
approach, our present method enables convenient preparation
of new N-phthaloyl substrates in good to excellent yields.
Asymmetric hydrogenation with a Rh-TangPhos system
afforded the products with excellent ee’s (up to 99% ee).
Although intensive efforts have been made for the
synthetic route to N-acyl enamides,7 fewer studies have
focused on the N-phthaloyl counterpart. This is not surprising
in view of its less basic nitrogen atom stabilized by the
neighboring two carbonyl groups. In a pioneering study,
Trost reported the use of catalytic PPh3 to activate the
alkynoate regioselectively at the R-position prior to nucleo-
philic addition of phthalimide, leading to 7 (R ) aryl or H)
in excellent yields.6 However, asymmetric hydrogenation of
this type of substrates was not pursued. Furthermore, aliphatic
analogues cannot be prepared via this route because of
competitive side reactions.
Figure 2. ORTEP representation of 6a (50% probability for the
drawing of thermal ellipsoids).
Despite the moderate yield (43%), this transformation is
unique in that, unlike a typical metal-catalyzed coupling
reaction, the phthalimide unit is assembled at the ꢀ-position
with concomitant elimination of an R-bromo group, presum-
ably through a tandem Michael addition-elimination reaction
sequence.10 To study its scope, a variety of ꢀ-aryl ꢀ-dehy-
droamino acid esters 4a-l were prepared under similar
conditions. As shown in Table 1, substitution on the phenyl
ring has a remarkable effect on the separation yield of 6.
While electron-withdrawing NO2 enhances the reaction
(entries 2 and 3), those bearing an electron-donating sub-
Table 1. Preparation of ꢀ-Aryl ꢀ-N-Phthaloyl 6a-la
To gain full access to these structurally interesting
compounds, it is necessary to explore alternative methods.
We chose vinyl bromide as starting material, which can be
easily prepared in a few steps via Wittig reaction.8 The
coupling of sp2-bromide with amide has been extensively
studied, usually involing transition metal catalyst.9 Instead
of resorting to those metal catalysts, we looked for a simple
conversion to the desired product. To our delight, it was
found through various tests that simply heating the solution
of 4a and 5 in DMF gave the product 6a (Table 1, entry 1).
Its configuration was determined as Z via X-ray diffraction
experiment (Figure 2).
entry
R
T (°C)/time (h)
6
yieldb (%)
Z:Ec
1
2
3
4
5
6
7
8
H
150/12
90/1
60/1
120/4
150/6
120/12
120/12
120/12
120/12
130/12
130/12
130/12
6a
6b
6c
6d
6e
6f
6g
6h
6i
43
92
95
87
58
40
45
67
62
80
76
67
>50:1d
>50:1d
>50:1d
>50:1d
1.1:1
4-NO2
3-NO2
4-Cl
2-Cl
2-Br
(4) (a) Lei, A.; Wu, S.; He, M.; Zhang, X. J. Am. Chem. Soc. 2004,
126, 1626. (b) Wang, C.-J.; Sun, X.; Zhang, X. Angew. Chem., Int. Ed.
2005, 44, 4933. (c) Yang, Q.; Gao, W.; Deng, J.; Zhang, X. Tetrahedron
Lett. 2006, 47, 821.
1.2:1
3-Br
>50:1d
1.5:1
(5) (a) Huang, H.; Liu, X.; Deng, J.; Qiu, M.; Zheng, Z. Org. Lett. 2006,
8, 3359. (b) Deng, J.; Duan, Z.-C.; Huang, J.-D.; Hu, X.-P.; Wang, D.-Y.;
Yu, S.-B.; Xu, X.-F.; Zheng, Z. Org. Lett. 2007, 9, 4825.
(6) Trost, B. M.; Dake, G. R. J. Am. Chem. Soc. 1997, 119, 7595.
(7) Zhao, H.; Vandenbossche, C. P.; Koenig, S. G.; Singh, S. P.; Bakale,
R. P. Org. Lett. 2008, 10, 505, and references therein.
2,4-di-Cl
4-NMe2
4-t-Bu
4-Et
9
>50:1d
>50:1d
3.7:1
10
11
12
6j
6k
6l
4-Me-O
>50:1d
(8) See Supporting Information for details.
a All reactions were carried out with 10 mmol of 4 and 15 mmol of 5
in 30 mL of DMF. b Isolated yield. c Determined by 1H NMR. d Estimated
on the basis of the detection limit of proton NMR.
(9) (a) Coleman, R. S.; Liu, P.-H. Org. Lett. 2004, 6, 577. (b) Jiang, L.;
Job, G. E.; Klapars, A.; Buchwald, S. L. Org. Lett. 2003, 5, 3667. (c) Shen,
R.; Porco, J.A., Jr Org. Lett. 2000, 2, 1333. (d) Ogawa, T.; Kiji, T.; Hayami,
K.; Suzuki, H. Chem. Lett. 1991, 1443.
3034
Org. Lett., Vol. 10, No. 14, 2008

stituent gave lower yield (entries 9-12). Sterically, an ortho-
substituent (entries 5, 6, and 8) usually resulted in relatively
low yield compared with para-substituted substrates (entries
4, 9-12). The existence of a meta-bromo group also lowered
the yield considerably. With the help of H NMR analysis,
the configuration of 6 can be assigned unambiguously. It
was found that most of the product 6 exist predominantly as
the (Z)-isomer except for 6e, 6f, 6h, and 6k.
Intrigued by this highly efficient reaction, we wondered
whether it could be applied to aliphatic vinyl bromides. Thus
4m-4o were prepared from the corresponding aldehydes and
subjected to the same reaction condition in the presence of
5. To our surprise, this time R-N-phthaloyl products 7a-7c
were obtained as the only major product (Table 2). When
in the hope that a similar tandem Michael addition-elimination
strategy could be implemented. Compared with vinyl bro-
mide 4, 9 is readily available from ꢀ-keto esters 8. To our
delight, the desired products 6m,n were obtained in moderate
yield after column chromatography (Table 3). From X-ray
Table 3. Preparation of ꢀ-Alkyl ꢀ-N-Phthaloyl 6m,na
entry
R
6
yieldb (%)
E:Zc
Table 2. Preparation of ꢀ-Alkyl R-N-Phthaloyl 7a-ca
1
2
Me
n-propyl
6m
6n
23
25
>50:1d
>50:1d
a All reactions were carried out with 1.4 mmol of 9 and 2.0 mmol of 5
in 5 mL of DMF at 90° for 12 h. b Isolated yield. c Determined by 1H NMR.
d Estimated on the basis of the detection limit of proton NMR.
diffraction experiment, their predominant configuration was
determined as E (Figure 4).
entry
R
7
yieldb (%)
Z:Ec
1
2
3
n-C3H7-
n-C5H11
n-C9H19
7a
7b
7c
82
63
62
>50:1d
>50:1d
>50:1d
-
-
a All reactions were carried out with 10 mmol of 4 and 15 mmol of 5
c
in 30 mL of DMF at 90°for an hour. b Isolated yield. Determined by H
1
NMR. d Estimated on the basis of the detection limit of proton NMR.
the alkyl chain becomes longer, the yield drops considerably.
Their major (Z)-configuration was assigned by H NMR
analysis and X-ray diffraction experiments (Figure 3).
Since our initial attempt to prepare the aliphatic analogues
of 6 failed, we switched to ꢀ-tosylates 9 as starting materials,
1
Figure 4. ORTEP representation of 6m (50% probability for the
drawing of thermal ellipsoids).
With all of these interesting substrates 6 and 7 at hand,
we performed brief asymmetric hydrogenation reactions.
Initial screening of chiral ligands for the substrate 6l, a typical
(Z)-ꢀ-dehydroamino acid ester, revealed TangPhos11a as the
most selective among several well-established ligands,
including DuanPhos11b and DuPhos.11c A number of com-
mon organic solvents were screened, which showed that
EtOAc was the solvent of choice. As seen from the selected
hydrogenation results (Table 4), all substrates have been
hydrogenated with excellent enantioselectivities by the Rh/
TangPhos system (up to 98% ee). In contrast, substrates 6e,
6f, 6h bearing ortho chloro or bormo groups deactivate the
catalyst, probably through phthalimide-assisted oxidative
addition of Rh into the C-X bond.12 Finally, this catalyst
was applied in the hydrogenation of R-dehydroamino acid
ester 7b and 7c, affording the product in 97% and >99%
ee, respectively (Table 5).
In summary, a series of N-phthaloyl dehydroamino acid
esters have been prepared via a novel reaction of vinyl
Figure 3. ORTEP representation of 7a (50% probability for the
drawing of thermal ellipsoids).
(10) See Supporting Information for discussion of the mechanism.
Org. Lett., Vol. 10, No. 14, 2008
3035

Table 4. Rh-Catalyzed Asymmetric Hydrogenation of 6 under
Various Conditions
Table 5. Rh-Catalyzed Asymmetric Hydrogenation of 7 under
Various Conditions
entrya
6
L/
solvent
10 conv (%)e ee (%)f, g (config)
entrya
7
L* solvent 11 conv (%)e ee (%)f, g (config)
1
2
3
4
5
6
7
8
6l
6l
6l
6l
6l
6l
6l
6l
6l
6l
L1b EtOAc
L2c EtOAc
10b
10b
10b
100
100
100
100
33
88
85
97 (-)
96
89
1
2
7b L3b EtOAc 11a
7c L3 EtOAc 11b
100
100
97 (+)
>99 (+)
L3
EtOAc
a All reactions were carried out with 0.1 mmol of substrate at room
temperature under a H2 pressure of 30 bar in 3 mL of the EtOAc for 20 h
with a substrate/[Rh(COD)L*]BF4 ratio of 1/0.01. b L3 ) (S,S,R,R)-TangPhos.
e Conversion was determined by 1H NMR. f The ee values were determined
by HPLC on a chiral column (see Supporting Information for details).
g Absolute configuration not determined.
L3d CH2Cl2 10b
L3
L3
L3
L3
L3
L3
acetone 10b
THF
EtOH
i-PrOH 10b
MeCN 10b
toluene 10b
EtOAc
EtOAc
EtOAc
EtOAc
10b
10b
100
100
100
0
87
96
96
n.a.
97
9
10
11
12
13
14
14
these structurally interesting compounds. Asymmetric hy-
drogenation with a Rh/TangPhos system gave excellent
results.
6a L3
6j L3
6k L3
6m L3
10a
10c
10d
10e
100
100
100
100
95 (-)
94 (-)
92 (-)
98 (+)
Acknowledgment. This work was supported by National
Institutes of Health (GM58832), National Nature Science
Foundation of China (20502020), China Scholarship Council,
and the startup fund from Wuhan University. Mass spec-
trometry was provided by the Washington University Mass
Spectrometry Resource, an NIH Research Resource (Grant
P41RR0954).
a All reactions were carried out with 0.1 mmol of substrate at room
temperature under a H2 pressure of 30 bar in 3 mL of solvent for 20 h with
a substrate/[Rh(COD)L*]BF4 ratio of 1/0.01. b L1 ) Et-DuPhos. c L2 )
(ScRp)-DuanPhos. d L3 ) (S,S,R,R)-TangPhos. e Conversion was determined
by 1H NMR. f The ee values were determined by HPLC on a chiral column
(see Supporting Information for details). g Absolute configuration not
determined.
Supporting Information Available: Synthesis of sub-
strates, hydrogenation, spectroscopic data, and experimental
details, including a file in CIF format. This material is
available free of charge via the Internet at http://pubs.acs.org.
bromide or vinyl tosylate with potassium bromide. Depend-
ing on the nature of the substituent (aryl or alkyl) on 7, the
phthalimide moiety can be selectively attached to either the
R- or ꢀ-position, thereby providing an efficient synthesis of
OL800996J
(11) (a) Tang, W.; Zhang, X. Angew. Chem., Int. Ed. 2002, 41, 1612.
(b) Liu, D.; Zhang, X. Eur. J. Org. Chem. 2005, 646. (c) Burk, M. J. Acc.
Chem. Res. 2000, 33, 363.
(12) No reduction by Rh/TangPhos was observed even at 60 °C under
120 bar hydrogen pressure.
3036
Org. Lett., Vol. 10, No. 14, 2008