Stereospecific, enantioselective allylation of α-hydrazono esters by using allyltrichlorosilanes with BINAP dioxides as neutral-coordinate organocatalysts

Article abstract of DOI:10.1002/anie.200461312

(Chemical equation presented). Excellent diastereo- and enantioselectivities were obtained in the title reaction, (E)-Crotylsilanes gave syn adducts, whereas anti adducts were obtained from (Z)-crotylsilanes (see scheme).

Full text of DOI:10.1002/anie.200461312

Angewandte
Chemie
hexamethylphosphoramide (HMPA) mediate allylation of
aldehydes[5] and N-acylhydrazones[6] with allyltrichlorosi-
lanes. Remarkably, the reactions proceeded without the use
of any metal catalyst. These organic molecules coordinate to
allyltrichlorosilanes to form hypervalent silicon compounds[7]
that react with electrophiles efficiently; thus, we defined these
molecules as neutral coordinate-organocatalysts (NCOs).[8]
Quite recently, we have achieved stereospecific, enantiose-
lective allylation of N-acylhydrazones by using chiral sulf-
oxides as chiral NCOs.[9] We have also found that phosphine
oxides are effective for the allylation of N-acylhydrazones.[10]
On the basis of this background, we decided to develop the
stereospecific, enantioselective allylation of a-imino ester
derivatives.
Asymmetric Synthesis
We selected a-hydrazono esters as a-imino ester surro-
gates because of their stability compared to the corresponding
a-imino esters. Indeed, most a-hydrazono esters are crystal-
line, easily purified by simple recrystallization, and can be
stored for several months at room temperature.[3,11] First, the
reaction of a-hydrazono ester 4a (prepared from ethyl
glyoxylate and benzhydrazide) with allyltrichlorosilane (5a)
was chosen as a model, and several enantiopure catalysts were
tested (Table 1). When sulfoxide 1 was used as a chiral
Stereospecific, Enantioselective Allylation of a-
Hydrazono Esters by Using Allyltrichlorosilanes
with BINAP Dioxides as Neutral-Coordinate
Organocatalysts**
Chikako Ogawa, Masaharu Sugiura, and
Shu¯ Kobayashi*
Enantioselective allylation of a-imino esters or their equiv-
alents provides one of the most efficient routes to optically
active natural and unnatural a-amino acids. Lectka et al.
reported enantioselective allylation of a hemiacetal of a N-
sulfonyl a-imino ester with trimethyl(2-phenylallyl)silane and
related silanes using a chiral CuI catalyst.[1] Jørgensen et al.
also reported at almost the same time that the chiral CuI
catalyst had lower activity for the reaction with allylsilanes.
His group used allylstannanes instead of allylsilanes.[2] How-
ever, in both cases, the enantioselectivities obtained were still
unsatisfactory, and were dependent on the structure of
allylsilanes. Recently, our group also reported that enantio-
selective allylation of a-hydrazono esters with allyltrimethoxy-
silanes proceeded smoothly in aqueous media in the presence
of a ZnF2-chiral diamine complex.[3] However, also in this case
the enantoselectivities obtained were less than 90% ee.
Furthermore, only a few examples of diastereo- and enantio-
selective addition of g-substituted allyl metals to a-imino
esters have been reported;[1b,2,4] no stereospecific, enantiose-
lective allylation has been attained to date.
Table 1: Optimization of reaction conditions.
Entry
NCO
x
Conc. [m]
Yield [%]
60
ee [%]
1
2
3
4
5
6
1
2
2
2
2
2
3.0
0.20.30
0.4
1.0
1.0
0.15
23 (S)
R)
69 (R)
R)
R)
98 (R)
11
56 (
0.30
0.30
0.05
0.05
38
6296 (
7295 (
91
2.0
Recently, we have found that neutral (uncharged) organic
molecules such as N,N-dimethylformamide (DMF) and
catalyst, the reaction proceeded to afford the desired allylated
adduct 6a in 60% yield but with disappointingly low
enantioselectivity (23% ee; Table 1, entry 1). Although
several reaction conditions were examined using 1, little
improvement of the yield and the selectivity was observed.
We then decided to search for other chiral catalysts for this
reaction. After screening several catalysts, we found that 2,2’-
bis(diphenylphosphanyl)-1,1’-binaphthyl dioxides (2, BINAP
dioxides) were promising. When 1.0 equivalent of (S)-BINAP
dioxide (2) was used in the reaction between 4a and 5a, the
reaction proceeded in dichloromethane at À788C to give the
desired adduct 6a in 62% yield with 96% ee (Table 1, entry
4). Unfortunately, use of smaller amounts of (S)-BINAP
dioxide gave lower yields and enantioselectivities (Table 1,
[*] Dr. C. Ogawa, Dr. M. Sugiura, Prof. Dr. S. Kobayashi
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax: (+81)3-5684-0634
E-mail: skobayas@mol.f.u-tokyo.ac.jp
[**] This work was partially supported by CREST, SORT, ERATO, the
Japan Science Technology Corporation (JST), and a Grant-in-Aid for
Scientific Research from the Japan Society of the Promotion of
Sciences (JSPS). BINAP=2,2’-Bis(diphenylphosphanyl)-1,1’-
binaphthyl.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 6491 –6493
DOI: 10.1002/anie.200461312
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6491

Communications
entries 2 and 3). The yield and the selectivity were further
The present allylation was successfully applied to the
enantioselective synthesis of d-alloisoleucine, an uncommon
a-amino acid observed in biologically important peptides;[15]
however, there are several reports on enantioselective syn-
thesis of this molecule.[16] Our synthesis is outlined in
Scheme 1. The starting material 6e is an allylated adduct
improved when two equivalents of 2 were used under lower
concentration conditions; thus, the desired adduct 6a was
obtained in 91% yield with 98% ee (Table 1, entry 6). After
the reaction, 2 was recovered almost quantitatively without
loss of optical purity. It is noted that the use of chiral
phosphine oxides in asymmetric catalysis has been limited,[12]
whereas innumerable usage of BINAP has been reported.[13]
We then examined other a-hydrazono esters and allyltri-
chlorosilanes, and the results are summarized in Table 2. For
Table 2: Allylation of a-hydrazono esters by using BINAP dioxides.
Scheme 1. Facile synthesis of d-alloisoleucine.
prepared from 4a and 5b (Table 2, entry 5). The olefin moiety
of 6e was reduced by using polymer incarcerated Pd (PI
Pd)[17] to give 7 in 70% yield. Successive reductive cleavage of
the N N bond of 7 using SmI2,[18] followed by ester hydrolysis
À
gave d-alloisoleucine (quantitative yield for two steps). Thus,
d-alloisoleucine has been synthesized from a-hydrazono ester
4a in four steps in an overall yield of 64%. This efficient
synthesis demonstrates the utility of the BINAP dioxide-
catalyzed enantioselective allylation reaction for amino acid
synthesis.
Entry Electrophile Silane Yield [%] syn/anti
ee [%]
1
2
3
4
5
6
4a
4b
4c
4d
4a
4a
4a
4a
4a
4a
5a
5a
5a
5a
5b
5c
5d
5e
5 f
91 (6a)
70 (6b)
2 8 (6c)
12( 6d)
92( 6e)
96 (6 f)
80 (6g)
80 (6h)
83 (6i)
50 (6j)
–
–
–
–
98 (R)
97
98
91
98/2
>99 (2R, 3S)
<1/>99 96 (2R, 3R)
98/296 (2 S, 3R)
<1/>99 81 (2S, 3S)
–
–
In conclusion, we have found that BINAP dioxides are
excellent chiral neutral-coordinate organocatalysts for the
enantioselective allylation of a-hydrazono esters using allyl-
trichlorosilanes. The reactions proceeded stereospecifically;
(E)-allylic silanes gave syn adducts, whereas anti adducts were
obtained from (Z)-allylic silanes. This is the first example of
the stereospecific, enantioselective allylation of a-imino ester
equivalents. Diastereo- and enantioselectivies obtained in this
allylation are very high compared to those reported by
previous methods. In addition, the present reaction was
successfully applied to the efficient synthesis of d-alloisoleu-
cine. A drawback of this reaction is the use of two equivalents
of BINAP dioxides, but the chiral source could be recovered
almost quantitatively without loss of optical purity. Further
investigations to reduce the amounts of BINAP dioxides are
now in progress.
7[a]
8[a]
9[b]
10[a]
94 (R)
95
5g
[a] Compound 3 was used instead of 2. Reaction time was 15 h.
[b] Reaction time was 6 h.
a-hydrazono esters, larger ester groups gave lower yields,
whereas high enantioselectivities were maintained in some
cases. For allyltrichlorosilanes, we carefully examined croty-
lation using (E)- and (Z)-crotyltrichlorosilanes. It was excit-
ing to find that the reactions proceeded stereospecifically;
(E)-crotyltrichlorosilane 5b gave the syn adduct 6e (Table 2,
entry 5), whereas the anti adduct 6 f was produced from (Z)-
crotyltrichlorosilane 5c (Table 2, entry 6).[14] In both cases,
yields were high, and excellent diastereo- and enantioselec-
tivities were obtained. When (E)- and (Z)-allylic trichlorosi-
lanes, 5d and 5e, were employed, both syn and anti adducts
were also obtained stereospecifically, although (R)-2,2’-bis(di-
p-tolylphosphanyl)-1,1’-binaphthyl dioxides (3, (R)-p-tol-
BINAP dioxides) as an NCO gave better results than 2
(Table 2, entries 7 and 8). It is noteworthy that this is the first
example of stereospecific, enantioselective allylation of a-
imino ester equivalents. Other allylic silanes 5 f and 5g also
worked well to afford the desired adducts with high enantio-
selectivities (Table 2, entries 9 and 10).
Received: July 15, 2004
Keywords: allylation · amino acids · asymmetric catalysis ·
asymmetric synthesis · hydrazones
.
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Chemie
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