Chiral zinc-catalyzed asymmetric α-alkylallylation and α-chloroallylation of aldehydes

Article abstract of DOI:10.1002/anie.201106433

Two birds with one stone: In the presence of Zn(OH)₂ and a chiral bipyridine ligand, racemic α-substituted allylboronates 2 reacted with aldehydes 1 (see scheme) exclusively in an α-addition fashion to afford various homoallylic alcohols 3 bear

Full text of DOI:10.1002/anie.201106433

Communications
DOI: 10.1002/anie.201106433
Asymmetric Catalysis
Chiral Zinc-Catalyzed Asymmetric a-Alkylallylation and
a-Chloroallylation of Aldehydes**
Shu¯ Kobayashi,* Toshimitsu Endo, and Masaharu Ueno
Asymmetric catalysis is now recognized as one of the most
efficient methods for the preparation of optically active
compounds.[1] Although many catalytic asymmetric reactions
have been developed, most reactions are carried out under
strictly anhydrous and oxygen-free conditions, because most
chiral catalysts and reagents decompose in the presence of
even small amounts of water or oxygen. Furthermore, many
reactions are conducted at low temperature, such as À788C,
to obtain high selectivities. It is energy efficient and thus
preferable to perform reactions at 08C to ambient temper-
ature.
Asymmetric allylation of aldehydes provides optically
active homoallylic alcohols, which are useful intermediates
for the synthesis of natural products, biologically important
compounds, and so forth.[2] When substituted allylating
reagents are used, it is possible to control the absolute
configuration of two successive stereogenic centers during
one carbon–carbon bond formation. For catalytic asymmetric
allylation of aldehydes (using substoichiometric amounts of
chiral sources) allylstannanes[3] and allylsilanes[4] have often
been used as allylating reagents.[5] However, allylstannanes
are toxic and allylsilanes are less reactive and sometimes have
narrow substrate scope. More recently, allylboron reagents
have received attention as reactive and less toxic allylating
reagents in asymmetric catalysis.[6,7a–d] However, although
allylboron reagents have been successfully used for allylation
of less reactive ketones,[6j–l] because of their high reactivity the
reactions with aldehydes proceeded instantaneously without
catalysts,[7c] and therefore catalytic asymmetric reactions of
aldehydes with allylboron reagents have been carried out at
low temperature (mostly at À788C). Moreover, examples of
catalytic asymmetric a-alkylallylation and a-chloroallylation
of aldehydes with allylboron reagents to construct two
successive stereogenic centers are very rare, and to our
knowledge only catalytic asymmetric a-methylallylation
(crotylation) using crotylboronates has been reported.[5b,e–i,6f,7]
Recently, we found that allylation reactions of allylboro-
nates with aldehydes proceed smoothly in the presence of
catalytic amounts of Zn(OH)2 and 2,9-dimethyl-1,10-phenan-
throline (dmp) in aqueous media.[8] When a-substituted
allylboronates such as 2a were employed, the a-addition
products were obtained exclusively with syn selectivities.
As an extension of this work, we have investigated a
catalytic asymmetric variant of this reaction. After the
investigation of various chiral ligands and allylboronates, it
was found that the combination of Zn(OH)2 and the chiral
bipyridine ligand 4[9] with allylboronic acid 2,2-dimethyl-1,3-
propanediol ester (2b) gave the best results. A certain amount
of g-adduct was obtained with the allylboronic acid pinacol
ester (2a), whereas in the reaction with 2b the desired a-
addition product was obtained exclusively with excellent syn
selectivity and good enantioselectivity (Table 1).
Table 1: Optimization of reaction conditions.
Entry Allylboronate Yield [%][a] a/g[b]
syn/anti[b] e.r. (syn)[c]
1
2
2a
2b
2b
2b
2b
75
96
92
92
85
52/48
94/6
89/11
>99/<1 10/1
>99/<1 10/1
19/1
10/1
16/1
83/17
81/19
86/14
3[d]
4[e]
5[e,f]
85.5/14.5
86.5/13.5[g]
1
[a] Yield of isolated product. [b] Determined by H NMR spectroscopy.
[c] Determined by HPLC on a chiral stationary phase. [d] 08C. [e] 08C. 1a
was added over one hour. [f] 4-ent was used. [g] The enantiomer of 3a is
the major product.
Other examples of chiral zinc-catalyzed asymmetric a-
alkylallylation and a-chloroallylation are shown in Table 2.
The reactions proceeded smoothly using 2–10 mol% of the
catalyst, and in all cases exclusive a-selectivity was observed
at 08C in aqueous media. A gram-scale preparation is also
possible. Not only a-methylallylation (crotylation) but also
other a-alkylallylations proceeded smoothly, and moderate to
excellent syn selectivities and high to excellent enantioselec-
tivities were obtained (Table 2, entries 1–7). Moreover, a-
benzyloxyallylation also proceeded well under the conditions,
and high yields and diastereo- and enantioselectivities were
attained using both aromatic and aliphatic aldehydes
[*] Prof. Dr. S. Kobayashi, T. Endo, Dr. M. Ueno
Department of Chemistry, School of Science
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo, 113-0033 (Japan)
E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
[**] This work was partially supported by a Grant-in-Aid for Scientific
Research from the Japan Society for the Promotion of Science
(JSPS), ERATO (JST), NEDO, and GCOE. We would also like to
thank Mr. Takeshi Naito (The University of Tokyo) for the X-ray
crystal-structure analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201106433.
12262
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Angew. Chem. Int. Ed. 2011, 50, 12262 –12265

Table 2: Asymmetric a-alkylallylation and a-chloroallylation.[a]
smoothly with aldehydes in a g-addition fashion. A kinetic
investigation revealed a first-order dependence on the con-
centration of allylboronate and a zero-order dependence on
the concentration of electrophile.[13] Our analysis leads us to
conclude that transmetalation from B to Zn is the rate-
determining step in this reaction. Another characteristic
feature of this catalytic process is that the reactions proceeded
smoothly in aqueous media, where water plays a key role to
facilitate release and regeneration of the catalyst from the
products.
Entry R1
R2
Loading Yield
(mol%) [%][b]
syn/
e.r.
anti[c] (syn)[d]
1
2
3
4
PhCH2CH2
Me
Me
Me
Me
Et
iBu
nBu
OBn 10
OBn 10
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
10
5
3
3
5
94
94
94
80
96
95
97
82
74
93
92
91
99
6/1
5/1
7/1
5/1
3/1
94/6
92.5/7.5
91/9
98.5/1.5
95.5/4.5
95.5/4.5
95/5
94/6
98/2
94/6
94/6
93.5/6.5
95.5/4.5
92.5/7.5
93/7
92.5/7.5
98.5/1.5
97.5/2.5
97/3[g]
99/1
PhCH2CH2
CH3(CH2)8
c-C6H11
PhCH2CH2
PhCH2CH2
PhCH2CH2
Ph
PhCH2CH2
Ph
Ph
4-MeC6H4
3-MeOC6H4
4-BrC6H4
1-naphthyl
1-naphthyl
PhCH2CH2
PhCH2CH2
PhCH2CH2
CH3(CH2)10
CH3(CH2)10
CH3(CH2)10
(CH3)2CHCH2
We also conducted an X-ray crystal-structure analysis.
Single crystals that were suitable for X-ray analysis were
obtained from a ZnBr2-4 complex (Figure 1).[14] The complex
5[e]
6[e]
7[e]
8
5
5
3/1
3/1
24/1
4/1
99/1
24/1
24/1
19/1
9
10
11
12
13
14
15
16
17
18
19[f]
20
21
22
23
24
10
5
3
7.5
7.5
10
5
10
3
3
10
3
2
10
10
quant. 19/1
quant. 19/1
94
85
92
87
93
93
92
64
73
13/1
19/1
13/1
13/1
32/1
13/1
13/1
49/1
7/1
Figure 1. X-ray structure of ZnBr2-4-ent complex.
96.5/3.5
96.5/3.5
99/1
adopts a square-pyramidal structure, in which the two
pyridine nitrogen atoms and one of the two hydroxy groups
of 4 coordinate to Zn2+. It is interesting that one of the two
hydroxy groups of 4 does not coordinate to Zn2+ in this
structure.[15,16] It is likely that the two Br groups dissociate in
aqueous media, and it may be possible that the square-
pyramidal structure converts to the trigonal-pyramidal struc-
ture in solution.[17] In any case, if one of the Br atoms is
replaced by an allyl group by transmetalation from B to Zn in
a g-addition fashion, one face of the allylzinc moiety could be
shielded by the fixed tert-butyl group (left in Figure 1). This
transition state model is consistent with the absolute config-
uration of the products obtained. We also evaluated chiral
ligands 5 and 6 in the reaction of 3-phenylpropanal with a-
chloroallylboronate (2, R2 = Cl) under the standard condi-
tions (Table 3). Very interestingly, in both cases the reactions
proceeded smoothly exclusively in an a-addition fashion, but
almost no selectivity was observed using 6, whereas the same
high diastereo- and enantioselectivities as obtained using
ligand 4 were obtained using 5. Furthermore, these results
contrast strikingly with our previous results in an asymmetric
ring-opening reaction of a meso-epoxide with aniline, where
almost no diastereo- or enantioselectivity was obtained using
either 5 or 6.[18]
TBSO-CH2CH2 Cl
96/4
[a] Compound 1 was slowly added over one hour unless otherwise noted.
The a/g ratio was determined by 1H NMR spectroscopy and found to be
>99/<1 in all cases. [b] Yield of isolated product. [c] Determined by
1H NMR spectroscopy. [d] Determined by HPLC on a stationary phase.
[e] 1 was added over three hours. [f] 4-ent was used. [g] The enantiomer
of 3 is the major product.
(Table 2, entries 8 and 9). This Zn catalysis was also appli-
cable to asymmetric a-chloroallylation (Table 2, entries 10–
24). Optically active a-chlorohomoallylic alcohols (3; R2 =
Cl) are useful intermediates for the synthesis of natural
products and other compounds (see below). Aromatic as well
as aliphatic aldehydes bearing some functional groups worked
efficiently to afford the desired products in high to excellent
yields with high to excellent diastereo- and enantioselectiv-
ities. Because both enantiomers of ligand 4 are readily
available, both enantiomers of the products can be easily
obtained according to this protocol (Table 2, entry 19, see also
Table 1, entry 5). The reaction also proceeded smoothly in the
presence of 2 mol% of the catalyst (Table 2, entry 22). It is
noteworthy that some of the products were directly used for
the synthesis of natural products, such as disparlure[10]
(Table 2, entries 20–22) and spirastrellolide A[11] (Table 2,
entry 24).
In summary, we have developed chiral zinc-catalyzed
asymmetric a-alkylallylation and a-chloroallylation of alde-
hydes. Various homoallylic alcohols bearing two neighboring
stereogenic centers were synthesized in high yields with high
diastereo- and enantioselectivities. The reactions proceeded
at 08C in an a-addition fashion exclusively with high
stereoselectivities in aqueous solution.[19] It is noteworthy
from a practical point of view that a low temperature such as
À788C and anhydrous conditions are not necessary. More-
The mechanism of this catalytic process has not yet been
completely elucidated; however, because a-addition products
were obtained exclusively, we assumed the double g-addition
mechanism operated.[8] A key species is assumed to be g-
substituted allylzinc with chiral ligand 4,[12] which can react
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Communications
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Table 3: Effect of ligands 4–6 in asymmetric a-chloroallylation of 3-
phenylpropanal.[a]
Entry
Ligand
Yield [%][c]
syn/anti[d]
e.r. (syn)[e]
1[b]
2
3
4
5
6
85
91
93
19/1
32/1
1/1.2
98.5/1.5
97.5/2.5
50.5/49.5
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[a] The reaction conditions are shown in Table 2 (Zn(OH)2 10 mol%,
ligand 12 mol%). The a/g ratio was determined by 1H NMR spectros-
copy and found to be >99/<1 in all cases. [b] The same as Table 2,
entry 17. [c] Yield of isolated product. [d] Determined by 1H NMR
spectroscopy. [e] Determined by HPLC on a stationary phase.
over, Zn(OH)2 used in this reaction as a catalyst is a common
compound, and the combined use with less toxic boron
reagents makes the whole process environmentally benign.
Furthermore, a-addition is a rare case of asymmetric allyla-
tion with allylboron reagents.[8,20] It is noted that optically
active boron reagents 2[21] are not needed, and that racemic 2
and a catalytic amount of a chiral source efficiently gave
optically active homoallylic alcohols with neighboring ste-
reogenic centers.
Received: September 11, 2011
Published online: October 25, 2011
Keywords: a-addition · aldehydes · allylation ·
.
asymmetric catalysis · synthetic methods
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