Enantiomerically enriched allylglycine derivatives through the catalytic asymmetric allylation of iminoesters and iminophosphonates with allylsilanes

Article abstract of DOI:10.1002/anie.200504196

(Chemical Equation Presented) α-Amino acid derivatives are obtained in high yields through the catalytic enantioselective allylation of iminoesters using environmentally benign allylsilanes as nucleophiles in the presence of a copper complex prepared from

Full text of DOI:10.1002/anie.200504196

Angewandte
Chemie
Amino Acid Synthesis
Allylation reactions of N-acyliminoester 1 with several
allylating reagents were examined in the presence of a copper
complex (10 mol%) prepared from Cu(OTf)2 and diamine 3,
which was an efficient catalyst for Mannich-type reactions of
iminoesters with silicon enolates.[2f,g] Relatively reactive
allyltributylstannane (2a) was found to give the desired
product, albeit in low yield with low selectivity (Scheme 1,
Eq. (1)). On the other hand, when allylsilane 2b, which bears
a sulfur substituent at the b-position to the silicon atom, was
employed[4] the allylated product was obtained in high yield
with high selectivity [Scheme 1, Eq. (2)].
DOI: 10.1002/anie.200504196
Enantiomerically Enriched Allylglycine
Derivatives through the Catalytic Asymmetric
Allylation of Iminoesters and Iminophosphonates
with Allylsilanes**
Hiroshi Kiyohara, Yoshitaka Nakamura,
Ryosuke Matsubara, and Shu¯ Kobayashi*
The synthesis of a-amino acids is one of the most important
topics in modern medicinal chemistry.[1] Among the variety of
synthetic methods so far reported, asymmetric carbon–carbon
bond-forming reactions of iminoesters provide an efficient
route to optically active a-amino acids. While catalytic
asymmetric Mannich-type reactions of N-protected iminoest-
ers have already been reported by several groups,[2] few
examples of catalytic asymmetric allylations of iminoesters
are known despite their utility in organic synthesis.[3] Lectka
and co-workers reported that N,O-acetals react with b-
phenylallyltrimethylsilane in the presence of a CuI/binap
(binap = 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl) com-
plex,[3a] and they also disclosed reactions of N-tosyl iminoest-
ers with b-arylallyltrimethylsilanes as well as nonsubstituted
allyltrimethylsilane under similar conditions.[3d] However,
only b-arylallylsilane gave the desired product with high
enantiomeric purity while other allyltrialkylsilanes gave
moderate selectivities (up to 72% ee). Jørgensen and co-
workers reported highly enantioselective reactions of N-tosyl
iminoesters with allyltributyltin.[3b,c] They showed that the use
of allylsilanes resulted in low yields with low selectivity.
Additionally, from a viewpoint of synthetic utility, a sulfonyl
group at the nitrogen center is sometimes problematic for
deprotection compared to amide or alkoxycarbonyl groups.
Hence, the development of environmentally friendlier, effi-
cient, and practical methods is strongly desired. Herein, we
report a CuII-catalyzed, highly enantioselective allylation of
N-acyl and N-alkoxycarbonyl iminoesters using environmen-
tally benign allylsilanes as nucleophiles. The first example of
catalytic enantioselective allylations of iminophosphonates
for the synthesis of a-aminophosphonic acids and their
phosphonate esters is also described.
Scheme 1. Allylation reactions of iminoester 1 with several allylating
reagents 2 catalyzed by CuII/3. Bn=benzyl; Tf=trifluoromethanesul-
fonyl; Nap=a-naphthyl.
However, the result was not reproducible (66–76% yield,
68–80% ee) especially in terms of selectivity. To address this
issue, we then examined the addition of dehydrating agents as
well as several procedures to add the substrates (Table 1). The
addition of 3-Š molecular sieves (3Š MS) and slow addition
of the substrates were found to improve the yield, selectivity,
and reproducibility (84% yield, 86% ee; entry 4, Table 1).
The 3Š MS were essential for the removal of water, which
Table 1: CuII/3-catalyzed reactions of iminoester 1b with allylsilane 2b.
[*] H. Kiyohara, Y. Nakamura, R. Matsubara, Prof. Dr. S. Kobayashi
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Entry
MS
T [8C]
Yield [%]
ee [%]
The HFRE Division, ERATO
1
2
3
–
0
66–76
44
56
84
77
68–80
87
80
86
80
Japan Science Technology Agency (JST)
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax: (+81)3-5684-0634
3Š
3Š
3Š
4Š
5Š
3Š
0
À20
0
4[a]
5[a]
6[a]
7[a,b]
E-mail: skobayas@mol.f.u-tokyo.ac.jp
0
0
0
[**] This work was partially supported by a Grant-in-Aid for Scientific
Research from the Japan Society of the Promotion of Sciences
(JSPS). H.K. and R.M. thank the JSPS for Fellowships for Japanese
Junior Scientists.
70
76
85
93
[a] Allylsilane 2b (1.36 equiv) was also slowly added (see Supporting
Information). [b] Toluene was used as a cosolvent. MS=molecular
sieves.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Communications
may induce partial hydrolysis of nucleophile 2b to form a
ceeded smoothly to afford the desired allylated adduct in
excellent yield and with moderate selectivity. After optimi-
zation, the selectivity was improved to 88% ee (entry 8,
Table 2). These optimal conditions were found to be appli-
cable to the reaction with allyltrimethylsilane 2 f (entry 9,
Table 2).[5]
Furthermore, we were pleased to find that this catalyst
system could be successfully applied to allylations of imino-
phosphonate 5 (Table 3). As reported previously,[6] the
catalyst turnover frequency was lower in reactions of
thiol (a potential copper poison). A lower temperature was
not beneficial for this reaction (entry 3, Table 1). Slow
addition of the substrates suppressed an uncatalyzed back-
ground reaction that otherwise furnished racemic product
(entry 5, Table 1). Of the molecular sieves tested, 3Š MS were
found to be superior to 4Š and 5Š MS. The best enantiose-
lectivity (93% ee; entry 7, Table 1) was obtained when
toluene was used as a co-solvent in the presence of 3Š MS
and when both substrates were simultaneously added to the
catalyst solution over 30 min.
Under these optimal conditions, various combinations of
electrophiles and nucleophiles were then examined (Table 2).
The use of allylsilane 2c also led to a high yield with high
selectivity (entry 2, Table 2). While N-acetyl iminoester 1c
gave high selecitivity (entry 3, Table 2), less reactive allylsi-
lane 2d afforded the desired product in good yield with high
selectivity (entry 4, Table 2). Additionally, methallyltrimeth-
ylsilane (2e) gave a lower yield with high selectivity, and only
a trace amount of the desired product was obtained when
allyltrimethylsilane (2 f) was treated with iminoester 1b under
the same conditions. These results, regarding yields, are
consistent with a relative reactivity of allylsilane nucleophiles
2b–f (entries 1–6, Table 2). Allylsilanes 2b and 2c also
reacted with N-Boc iminoesters smoothly to afford the
desired adducts in good yields with high selectivities
(entries 10 and 11, Table 2).
Table 3: CuII/3a-catalyzed reactions of iminophosphonate 5 with allylsi-
lanes 2.
Entry
2
Addition of 2
Product
Yield [%]
ee [%]
1[a,b]
2[a,b]
3[c]
2b: R=SEt
2c: R=SPh
2d: R=Ph
2e: R=CH3
2 f: R=H
0.14+1.36
0.14+1.36
1.5+0
1.5+0
1.5+0
6a
6b
6c
6d
6e
80
86
71
73
66
82
79
85
89
80
4[c]
5[c]
[a] CH2Cl2 as the solvent. [b] Simultaneous slow addition of 2. [c] CH2Cl2/
THF. Troc=trichloroethyloxycarbonyl.
We presumed the formation of a [4+2]-type self-conden-
sation adduct of iminoester 1b when less-nucleophilic allylsi-
lanes were employed. We thought at this stage that if less-
electrophilic iminoesters were used instead of 1b, then the
self-condensation may be suppressed and even less nucleo-
philic allylsilanes may react with iminoesters to afford the
desired adducts. On the basis of this assumption, we
conducted the reaction of N-Cbz iminoester 1d with meth-
allyltrimethylsilane (2e). To our delight, the reaction pro-
iminophosphonates than in those of iminoesters. Therefore,
slow addition of the electrophile was also essential in this
allylation reaction. Note that even less reactive allylsilanes
such as 2e and 2 f afforded the desired products in good yields
and with high enantioselectivities, and that highly enantiose-
lective allylation of an iminophosphonate was attained for the
first time.
In summary, highly enantioselective and efficient allyla-
tion reactions of iminoesters and an iminophosphonate using
various allylsilanes, catalyzed by a copper
complex prepared from Cu(OTf)2 and
Table 2: Substrate scope for CuII/3-catalyzed reactions of iminoesters 1 with allylsilanes 2.
chiral diamine 3, have been developed.
Whereas the study of catalytic asymmetric
allylations with iminoesters was relatively
neglected in relation to the corresponding
Mannich-type reactions, this study provides
a useful method for the preparation of a
variety of amino acids as well as amino-
phosphonic acids based on the allylation
protocol. Further investigations to improve
the yields and enantioselectivity by optimi-
zation of the ligand are currently in prog-
ress.
Entry
1
2
Addition of 2[a]
Product
Yield [%]
ee [%]
1[b,c]
2[b,c]
3[c,d]
4[c,d]
5[d]
1b: R1 =C11H23CO
1b: R1 =C11H23CO
1c: R1 =CH3CO
1b: R1 =C11H23CO
1a: R1 =C11H23CO
1a: R1 =C11H23CO
1d: R1 =Cbz
2b: R2 =SEt
2c: R2 =SPh
2b: R2 =SEt
2d: R2 =Ph
2e: R2 =CH3
2 f: R2 =H
0.14+1.36
0.14+1.36
0.14+1.36
0.5+1.0
3.0+0
3.0+0
3.0+0
3.0+0
3.0+0
4b
4c
4d
4e
4 f
4g
4h
4h
4i
76
84
75
68
33
trace
94
99
73
84
71
93
92
90
91
90
–
63
88
88
86
86
6[d]
7[d]
2e: R2 =CH3
2e: R2 =CH3
2 f: R2 =H
Received: November 24, 2005
Published online: January 30, 2006
8[e]
1d: R1 =Cbz
9[e]
1d: R1 =Cbz
10[b,c]
11[b,c]
1e: R1 =Boc
2b: R2 =SEt
2c: R2 =SPh
0.14+1.36
0.14+1.36
4j
4k
1e: R1 =Boc
[a] For example, for entry 1, 0.14 equiv of 2b was added initially, followed by the slow addition of a further
1.36 equiv of 2b simultaneously with 1 (see Supporting Information for details). [b] CH2Cl2/toluene.
[c] Simultaneous slow addition of 2. [d] CH2Cl2 as the solvent. [e] CH2Cl2/THF. Cbz=benzyloxycarbonyl;
Boc=tert-butoxycarbonyl.
Keywords: allylation · amino acids ·
asymmetric catalysis · iminoesters · synthetic
methods
.
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Chemie
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[5] See the Supporting Information for deprotection steps and
further transformations of the products.
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