Direct catalytic asymmetric mannich-type reactions of N-(2-hydroxyacetyl) pyrrole as an ester-equivalent donor

Article abstract of DOI:10.1002/anie.200501180

(Chemical Equation Presented) Stretching the limits of the Mannich reaction: A new indium-binol catalyst was used to generate the enolate of the esterequivalent donor in situ (see scheme). The donor, an N-acyl pyrrole, has many similarities to an aromatic ketone, in particular the enolates should have the same coordination mode. Versatile β-amino-α-hydroxy carboxylic acid derivatives were obtained in high yield and ee values.

Full text of DOI:10.1002/anie.200501180

Angewandte
Chemie
et al. achieved a highly enantioselective aldol reaction utiliz-
ing N-acyl thiazolidinethione donors and a chiral Ni cata-
lyst.[5a] The reaction proceeded with excellent yield and
selectivity; however, stoichiometric amounts of the silylating
reagent and amine base were required to facilitate catalyst
turnover. The development of a suitable ester-equivalent
donor and/or a new asymmetric catalyst to achieve both high
enantioselectivity and conversion without additional stoichio-
metric reagents is desirable. Herein, we report that an N-
acylpyrrole moiety is an effective achiral template for the in
situ generation of metal enolates. New complexes composed
of In(OiPr)3 and (S,S)-linked-binol 1 were used to catalyze the
asymmetric Mannich-type reaction of N-(2-hydroxyacetyl)-
pyrrole and ortho-tosylimines, which proceeded through
simple proton transfer to give b-amino-a-hydroxy carboxylic
acid derivatives in high enantioselectivity (91–98% ee, major
diastereomer) and good yield (65–98%).
Asymmetric Mannich Reaction
Direct Catalytic Asymmetric Mannich-Type
Reactions of N-(2-Hydroxyacetyl)pyrrole as an
Ester-Equivalent Donor**
We selected N-acylpyrrole as a donor substrate for
investigation and as an achiral template for the following
reasons. Evans et al. reported the unique properties of N-
acylpyrrole.[6] We subsequently demonstrated the utility of
the N-acylpyrrole moiety as an ester surrogate in catalytic
asymmetric conjugate additions, in which an a,b-unsaturated
N-acylpyrrole substrate was used as an activated, monoden-
tate electrophile.[7] Because the lone pair on the nitrogen
atom in the pyrrole ring is delocalized in an aromatic system,
the properties of the carbonyl group are similar to those of a
phenyl ketone. We supposed that N-acylpyrrole would also be
useful as an ester-equivalent donor because the aromaticity
would assist enolate formation. Since the coordination mode
of the N-acylpyrrole donor is similar to that of an aromatic
ketone, the chiral environment optimized for ketone donors
would be applicable for N-acylpyrrole. Based on our previous
report that the complex Et2Zn/linked-binol 1a is suitable for
the formation of an enolate from an aromatic hydroxyketo-
ne,[2c] we used N-(2-hydroxyacetyl)pyrrole 2 (Figure 1) and
complexes composed of a metal and linked-binol 1a in the
preliminary evaluations of the potential of the N-acylpyrrole
moiety for the catalytic in situ generation of metal enolates.
The results of the initial screening in the Mannich-type
reaction with 2 are shown in Table 1. When the Et2Zn/1a
Shinji Harada, Shinya Handa, Shigeki Matsunaga,* and
Masakatsu Shibasaki*
The catalytic in situ generation of metal enolates and
enamines from donor substrates in asymmetric carbon–
carbon bond-forming reactions has recently received much
attention.[1] Although tremendous progress has been made in
this area in the last five years with various metal catalysts and
organocatalysts,[2] room for improvement remains. For exam-
ple, in metal catalysis, the donor substrates are mostly limited
to ketones.[3,4] The use of donor substrates with the oxidation
state of carboxylic acid is still a formidable task since the pKa
value of the a proton in carboxylic acid derivatives is much
higher than that in ketones. A few landmark studies address-
ing this issue were recently reported.[5] In particular, Evans
[*] S. Harada, S. Handa, Dr. S. Matsunaga, Prof. Dr. M. Shibasaki
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax: (+81)3-5684-5206
E-mail: smatsuna@mol.f.u-tokyo.ac.jp
mshibasa@mol.f.u-tokyo.ac.jp
[**] This workwas supported by a Grant-in-Aid for Specially Promoted
Research and a Grant-in-Aid for Encouragement of Young Scientists
(B) (for S.M.) from JSPS and MEXT.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Figure 1. Structure and properties of N-acylpyrrole (2).
Angew. Chem. Int. Ed. 2005, 44, 4365 –4368
DOI: 10.1002/anie.200501180
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Table 1: Direct catalytic asymmetric Mannich-type reaction of N-(2-
afforded syn adducts in good diastereoselectivity (88:12–91:9)
and high enantioselectivity (93–97% ee (syn) Table 2,
entries 1–4). The syn selectivity of the reactions of imines
4e and 4 f, which have an unsubstituted and para-substituted
aromatic ring, respectively, was only modest (Table 2,
entries 5 and 6).[12] At present, this reaction with the In-
(OiPr)3/(S,S)-linked-binol complex is limited to sp2-hybri-
dized imines; however, subsequent functionalization of the
C–C double bond in the Mannich adducts obtained from
alkenyl imines 4a–d can afford b-alkyl-substituted b-amino-
a-hydroxy carboxylic acid derivatives (see below). Further
trials to expand the substrate scope of the reaction to aliphatic
imines are ongoing. On the other hand, imines 4g–k, which
contain ortho-substituted aromatic rings, and cyclopropyl
imine 4l gave products with anti selectivity[8] in high ee (92–
98% ee, anti; Table 3). Both electron-withdrawing (Cl, Br)
and electron-donating substituents (Me, MeO) on the aro-
hydroxyacetyl)pyrrole (2).[a]
Entry Imine Metal
Prod. t [h] Yield [%] syn/anti ee [%]
(x mol%)
1
2
3
3a
3a
4a
Et2Zn
(40)
In(OiPr)3 5a
(20)
In(OiPr)3 6a
(20)
5a
96
96
96
11
61
94
40:60
86:14
91:9
–
93
96
[a] PG=protecting group, MS 5Š=molecular sieves 5 Š, RT=room
temperature.
Table 2: Mannich-type reaction of imines 4a–f with 2.
complex was used for para-tosyli-
mine 3a, a Mannich adduct was
obtained in only low yield (Table 1,
entry 1, 11%), probably due to the
low Brønsted basicity of the Zn
catalyst in the formation of the zinc
enolate from 2. Screening of other
metal sources revealed that In-
(OiPr)3 was the most effective.[16]
When a 2:1 complex of In(OiPr)3
and 1a was used, the reaction of 2
and 3a in THFproceeded at room
temperature to give the Mannich
adduct in 61% yield and 93% ee
(Table 1, entry 2). The reaction of
ortho-tosylimine 4a under the
same conditions gave 6a with
improved yield (94%), diastereo-
selectivity (syn/anti = 91:9), and
enantioselectivity (96% ee (syn);
Table 1, entry 3).[8,9] In this reac-
tion, we assumed that either an
indium alkoxide or an indium
phenoxide functions as a Brønsted
base and deprotonates 2 at the a
position to form the indium eno-
late in situ. Although there are
many reports on Lewis acidic
indium catalysts (In(OTf)3, InCl3,
InBr3, etc.),[10] the Brønsted basic
property of indium chiral catalysis
was utilized for the first time in
organic synthesis. Furthermore, the
present reaction using an a-hy-
droxy-substituted donor comple-
ments the reports by Evans and
Entry
4, R
Lig. 1a
Prod.
t [h]
Yield [%]
d.r.
syn/anti
ee [%]
syn, anti
[x mol%]
1
2
3
4
5
6
4a, (E)-PhCH CH-
10
10
10
10
10
10
6a
6b
6c
6d
6e
6 f
96
97
97
99
111
89
94[a]
86[a]
79[a]
80
98
97
91:9
96, 83
95, 76
93, 71
97, 81
91, 91
96, 94
=
=
4b, (E)-p-tol-CH CH-
4c, (E)-p-Cl-C6H4-CH CH-
4d, (E)-2-furyl-CH CH-
89:11
88: 12
90:10
61:39
59:41
=
=
4e, Ph
4 f, p-Cl-C6H4-
[a] Yield of isolated product after conversion into the corresponding benzoate.
Table 3: Mannich-type reaction of 4g–l with 2.
Entry
4, R
Ligand
Prod.
t [h]
Yield [%]
d.r.
anti/syn
ee [%]
anti, syn
(x mol%)
1
2
3
4
5
6
7
8
9
4g, 1-naphthyl
4g, 1-naphthyl
4h, o-Cl-C6H4
4i, o-Br-C6H4
4j, o-Me-C6H4
4k, o-MeO-C6H4
4k, o-MeO-C6H4
4l, cyclopropyl
4l, cyclopropyl
1a (15)
1b (15)
1a (10)
1a (10)
1a (15)
1a (15)
1b (15)
1a (10)
1b (10)
6g
6g
6h
6i
99
99
76
89
92
93
93
65
65
86
87
87
68
76
70
74
83
86
72:28
77:23
83:17
86:14
76:24
77:23
77:23
63:37
75:25
90, 87
94, 89
93, 81
95, 90[a]
93, 85[a]
89, 81
92, 86
96, 91
98, 90
6j
6k
6k
6l
6l
[a] The enantiomeric excess was determined after conversion of the product into the triethylsilyl ether.
Shair,[5] in which a-alkyl-substituted donors were used.[11]
The substrate scope of the present reaction is summarized
in Tables 2 and 3. The diastereomeric ratio depended on the
imines used. As shown in Table 2, alkenyl imines 4a–d
matic ring were applicable. For less reactive substrates, an
increased amount of the chiral ligand (15 mol%) was
required to obtain products in good yield (Table 3, entries 1,
2, and 5–7). Use of a modified linked-binol ligand 1b resulted
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Chemie
in slightly better stereoselectivity in some cases (Table 3,
entries 1, 6, and 8 vs. 2, 7, and 9).
In all entries in Tables 2 and 3, the syn and the anti adducts
were obtained with the same absolute configuration at the
b position (S), implying that selection of the imine enantio-
face is identical.[8] Proposed models of the acyclic anti-
periplanar transition state are shown in Figure 2. Imines 4a–f
Scheme 1. Transformations of Mannich adducts. Reaction conditions:
a) NaOEt, EtOH, 08C!RT, 5 min, quant. yield; b) Pd/C, H2, MeOH,
RT, 30 min, 92%; c) pyrrolidine, DBU, THF, 408C, 1 h, quant. yield;
d) triphosgene, py, CH2Cl2, ꢀ788C!RT, 1 h, 94%; e) Mg powder,
MeOH, RT, 20 min, 81%; f) LDA, tBu acetate, THF, ꢀ788C, 10 min;
g) DBU, CH2Cl2, RT, 5 min, 62% (2 steps); h) TESCl, imidazole, DMF,
08C, 30 min, 87%; i) LiBH4, THF, RT, 30 min; j) (EtO)2P(O)CH2CO2Et,
LiCl, DBU, CH3CN, RT, 7 h, 67% (2 steps). DBU=1,8-diazabicyclo-
[5.4.0]undec-7-ene, py=pyridine.
Figure 2. Postulated transition-state model of Mannich-type reactions.
with a planar configuration would favor the TS-1 to minimize
gauche interactions. On the other hand, imines 4g–l have a
twisted configuration due to steric (4g–k) and stereoelec-
tronic (4l) effects. Thus, steric repulsion between imine
substituents R and the pyrrole ring of the indium enolate
would become more predominant, and the anti-periplanar
TS-2 would be more favorable than TS-1. For a more precise
understanding of the diastereoselectivity evidenced in Table 2
and Table 3 and the effects of the modified ligand 1b, further
mechanistic studies including clarification of the structure of
the complex of In(OiPr)3 and (S,S)-linked-binol 1 are
required.
Finally, the utility of the N-acylpyrrole unit as an ester
surrogate was demonstrated through several transformations
of Mannich adducts (Scheme 1).[13] The N-acylpyrrole unit of
6a was readily transformed into an ethyl ester unit by
treatment with NaOEt at room temperature for 5 min,
ated in situ from the crude pyrrole carbinol 13, and the a,b-
unsaturated ester 14 was obtained in 67% yield (in two steps
from the TES-protected Mannich adduct).
In summary, we have demonstrated the utility of N-
acylpyrrole 2 as an ester-equivalent donor in a direct
Mannich-type reaction. A catalytic amount of a chiral
complex composed of In(OiPr)3 and the (S,S)-linked-binol 1
was effective in generating the indium enolate in situ from 2.
The reaction is formally a simple proton transfer, and high
enantioselectivity (up to 98% ee) was achieved at ambient
temperature. Mechanistic studies of indium catalysis, trials to
improve the unsatisfactory reaction rate and diastereoselec-
tivity, and further application of the N-acylpyrrole moiety as
an ester-equivalent donor in other reactions are ongoing.
ꢀ
affording 7 in quantitative yield. Hydrogenation of the C C
double bond in 7 gave 8 in 92% yield, which corresponds to
the b-amino-a-hydroxy ester accessible from an aliphatic
imine. Substitution with amine also proceeded smoothly.
Amide 9 was obtained in quantitative yield by the treatment
of Mannich adduct 6e with pyrrolidine and DBU at 408C for
1 h. Neither epimerization nor racemization was observed
during substitution. After conversion of 9 into the cyclic
carbamate (94% yield), the o-Ts group was removed under
mild reduction conditions (Mg powder, room temperature,
20 min)[14] to give 10 in 81% yield. In addition to substitution
reactions with alcohols and amines, reaction of 6e with a
lithium enolate followed by treatment with DBU provided
keto ester 12 in 62% yield. Protection with a triethylsilyl
(TES) group followed by reduction with LiBH4 afforded the
pyrrole carbinol 13 as a stable intermediate. Under Masa-
mune–Roush conditions,[15] the aldehyde moiety was gener-
Received: April 4, 2005
Published online: June 7, 2005
Keywords: amino alcohols · asymmetric catalysis · indium ·
.
Mannich reaction · pyrroles
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Kumagai, S. Harada, M. Shibasaki, J. Am. Chem. Soc. 2003, 125,
[11] After submission of this manuscript, an excellent organocatalytic
Mannich reaction using a-oxyaldehydes was reported, see: a) I.
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(dimerization) reactions, see: b) A. B. Northrup, I. K. Mangion,
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[12] The diastereoselectivity of the reaction with the imine from
benzaldehyde was improved by using the bulkier 2,4,6-triiso-
propylbenzenesulfonyl imine (syn/anti = 78:22, syn: 95% ee);
however, reactivity decreased significantly (27% yield).
[13] For conversion of N-acylpyrrole units, see refs [6, 7], and
references therein.
[14] For the removal of Ts group using Mg powder, see ref. [2a]; see,
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[15] a) M. A. Blanchette, W. Choy, J. T. Davis, A. P. Essefeld, S.
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[16] Note added in proof: since submission of this manuscript we
have found that In(OiPr)3 can be purchased from Kojundo
Chemical lab (sales@kojundo.co.jp).
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[4] For exceptional examples in Mannich-type reactions using
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Kameda, J. Fujii, K. Maruoka, Org. Lett. 2004, 6, 2397; b) L.
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[5] Asymmetric aldol reactions: a) D. A. Evans, C. W. Downey, J. L.
Hubbs, J. Am. Chem. Soc. 2003, 125, 8706; b) Y. Suto, N.
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5, 3147; diastereoselective aldol reactions: c) D. A. Evans, J. S.
Tedrow, J. T. Shaw, C. W. Downey, J. Am. Chem. Soc. 2002, 124,
392; d) D. A. Evans, C. W. Downey, J. T. Shaw, J. S. Tedrow, Org.
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[6] a) D. A. Evans, G. Borg, K. A. Scheidt, Angew. Chem. 2002, 114,
3320; Angew. Chem. Int. Ed. 2002, 41, 3188; for the application
of N-acylpyrrole as a donor after conversion into enol silane, see:
b) D. A. Evans, D. S. Johnson, Org. Lett. 1999, 1, 595; c) D. A.
Evans, K. A. Scheidt, J. N. Johnston, M. C. Willis, J. Am. Chem.
Soc. 2001, 123, 4480.
[7] For the use of an a,b-unsaturated N-acylpyrrole as an electro-
phile, see: a) S. Matsunaga, T. Kinoshita, S. Okada, S. Harada,
M. Shibasaki, J. Am. Chem. Soc. 2004, 126, 7559; b) T. Kinoshita,
S. Okada, S. Matsunaga, Park, S.-R. Angew. Chem. 2003, 115,
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[8] For the determination of relative and absolute configurations of
Mannich adducts 6a–l, see the Supporting Information.
[9] The addition of MS 5 Š had beneficial effects on the reaction
rate but did not affect the enantiomeric excess. Similar effects of
molecular sieves were observed in related reactions using zinc
catalysts and hydroxy ketones as donors; see, a) S. Harada, N.
Kumagai, T. Kinoshita, S. Matsunaga, M. Shibasaki, J. Am.
Chem. Soc. 2003, 125, 2582; b) S. Matsunaga, T. Yoshida, H.
Morimoto, N. Kumagai, M. Shibasaki, J. Am. Chem. Soc. 2004,
126, 8777, and references therein; see also, refs [2b,c and 3b,c].
[10] Reviews: a) B. C. Ranu, Eur. J. Org. Chem. 2000, 2347; b) J.
Podlech, T. C. Maier, Synthesis, 2003, 633.
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