Catalytic enantioselective synthesis of sterically demanding alcohols using di(2°-alkyl)zinc prepared by the refined Charette's method

Article abstract of DOI:10.1039/c0cc01301c

A highly practical, catalytic enantioselective 2°-alkyl addition to aldehydes and ketones was developed. Chiral phosphoramide ligand (1) with salt-free and solvent-free di(2°-alkyl)zinc reagents prepared from (2°-alkyl)MgCl was essential. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/c0cc01301c

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Catalytic enantioselective synthesis of sterically demanding alcohols
using di(21-alkyl)zinc prepared by the refined Charette’s methodw
Manabu Hatano,a Tomokazu Mizunoa and Kazuaki Ishihara*ab
Received 9th May 2010, Accepted 3rd June 2010
First published as an Advance Article on the web 29th June 2010
DOI: 10.1039/c0cc01301c
A highly practical, catalytic enantioselective 21-alkyl addition to
aldehydes and ketones was developed. Chiral phosphoramide
ligand (1) with salt-free and solvent-free di(21-alkyl)zinc reagents
prepared from (21-alkyl)MgCl was essential.
Table 1 Optimization of the isopropylation of benzaldehydea
A catalytic enantioselective dialkylzinc addition to aldehydes
has been recognized as an effective method for synthesizing
optically active secondary alcohols.1 In particular, the 21-alkyl
addition to aldehydes with di(21-alkyl)zinc reagents has
become increasingly important in pharmaceutical chemistry
and in Soai’s autocatalysis with pyrimidine-5-carbaldehyde
and i-Pr2Zn.2 However, in sharp contrast to the di(11-alkyl)-
zinc addition to aldehydes, only a few limited examples of the
di(21-alkyl)zinc addition to aldehydes have been reported due
to steric constraint.3 Moreover, the lack of a commercially
available source of di(21-alkyl)zinc other than i-Pr2Zn has
discouraged work on the desired catalytic enantioselective
21-alkyl addition to aldehydes. Although convenient methods
have been reported for the preparation of dialkylzinc reagents
in situ, they are accompanied by the generation of mono-
alkylzinc complexes and/or inorganic salts, which sometimes
disturb subsequent reactions.4,5 To address this serious problem,6
we report here a catalytic enantioselective 21-alkyl addition
to aldehydes and ketones with salt-free and solvent-free di-
(21-alkyl)zinc reagents that are prepared from Grignard
reagents by using a refined Charette’s method.7
Molar ratio of
Yield
ee [%]
[%] of 3a of 3a
ZnCl2
:
NaOMe
:
i-PrMgCl
Entry
1b
2b
3b,c
4
1
1
1
1
1
1
1
:
:
:
:
:
:
:
2
2.5
2
:
:
:
:
:
:
:
1.9
1.9
1.6
1.6
1.6
1.6
1.6
90
88
73
93
94
93
84
3
0
91
91
94
93
92
2
5
2.5
2.5
2.5
6d
7e
a
Unless otherwise noted, salt-free i-Pr2Zn was used under solvent-free
b
conditions. i-Pr2Zn (0.44 M, in Et2O) was used. BnOH was obtained
c
d
e
in 26% yield. 10 mol% of ligand 1a in place of 1b was used. 3 mol% of
ligand 1a in place of 1b was used. Reaction time was 4 h.
73% yield with 91% ee (entry 3). However, an undesired
reduction byproduct (i.e. BnOH) was also obtained in 26%
yield (entry 3). Therefore, we examined the reaction under
solvent-free conditions11 by using salt-free liquid i-Pr2Zn
(bp. 134 1C),12 which was prepared by the same method followed
by the removal of Et2O in vacuo. As a result, 3a was obtained in
an improved yield (93%) with 91% ee, along with a trace amount
of BnOH (o2%) (entry 4). Moreover, with the use of 2.5 equiv.
of NaOMe,9 3a was obtained in 94% yield with 94% ee (entry 5).
Both less bulky 1b (10 mol%) and more bulky 1a (3 or 10 mol%)
Cote and Charette recently developed a highly useful method
´
for the preparation of salt-free di(11-alkyl)zinc reagents from
ZnCl2, NaOMe, and Grignard reagents.7 However, methods
for the preparation of salt-free di(21-alkyl)zinc reagents have
not yet been well-established. First, the isopropylation of
benzaldehyde (2a) was investigated with chiral phosphoramide
ligand 1b8 (10 mol%) (Table 1). By following a Charette’s
were effective in this reaction (entries 5–7). It was noted that Cote
´
typical procedure for the preparation of di(11-alkyl)zinc,7,9
a
and Charette used (2S)-(ꢀ)-3-exo-(N-morpholino)isoborneol
[(ꢀ)-MIB], which has been known as a representative chiral
ligand,13 in their asymmetric 11-alkylation to aldehydes.7 How-
ever, (ꢀ)-MIB was less effective than chiral ligand 1 in the
isopropylation of 2a (See the ESIw).
We next examined the catalytic enantioselective 21-alkyl
addition to various aldehydes under solvent-free conditions
with salt-free di(21-alkyl)zinc reagents derived from Grignard
reagents (Table 2). The isopropylation of aromatic aldehydes
(entry 1), heteroaromatic aldehydes (entries 2 and 3), and
cycloaliphatic aldehydes (entries 4 and 5) proceeded, and the
corresponding products were obtained in high yields with high
enantioselectivities (90–>99% ee). The isopropylation of tiglic
aldehyde as an a,b-unsaturated aldehyde provided only a
1,2-adduct (3g) with high enantioselectivity (97% ee) (entry 6).
Catalytic enantioselective sec-butylation also proceeded for
0.44 M solution of i-Pr2Zn in Et2O was prepared, but nearly
racemic 3a was obtained in 88–90% yield under Et2O con-
ditions (entries 1 and 2). We assumed that a small amount of
remaining Grignard reagent might trigger the racemic path-
way, since a highly active zinc(II) ate complex for alkylation,
namely [i-Pr3Zn]ꢀ[MgCl]+, would be generated in situ.10 As
expected, a conservative molar ratio of 1/2/1.6 of ZnCl2/
NaOMe/i-PrMgCl was effective, and 3a was obtained in
a Graduate School of Engineering, Nagoya University, Furo-cho,
Chikusa, Nagoya, 464-8603, Japan
b Japan Science and Technology Agency (JST), CREST, Furo-cho,
Chikusa, Nagoya, 464-8603, Japan. E-mail: ishihara@cc.nagoya-u.ac.jp;
Fax: +81-52-789-3331; Tel: +81-52-789-3222
w Electronic supplementary information (ESI) available: Experimental
details and product characterization. See DOI: 10.1039/c0cc01301c
ꢁc
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Table 2 Enantioselective 21-alkyl addition to aldehydes
To demonstrate the synthetic utility of this approach,
several transformations were examined. Compound 3n was
treated with N-bromosuccinimide in THF–H2O,16 and the
desired cyclohexyl-substituted 6-hydroxy-2H-pyran-3-one 417
was obtained via the oxidative Achmatowicz rearrangement in
89% yield with a diastereomeric ratio of 73 : 27 with 84% ee
(eqn (1), left). Moreover, after the TBS-protection of the
hydroxy group of 3n, ozonolysis cleavage of the furan ring
provided a-alkoxy carboxylic acid 518,19 in 96% yield (eqn (1),
right).
Yield
and ee
Yield
and ee
EntryProduct (3)
EntryProduct (3)
95%,
96% ee
90%,
99% ee
1a
3b
3c
3d
3e
3f
10b
3k
3l
ð1Þ
>99%,
95% ee
89%,
97% ee
2a
3
11a,c
12a,c
13c
By ozonolysis and subsequent Me2S treatment,20 allyl alcohol
3r was converted to a-hydroxy ketone 621 in 98% yield with
99% ee (eqn (2)). This is synthetically important because
compound 6 cannot be prepared directly from unstable
methylglyoxal by alkylation. In the same way, a-hydroxy ketone
7 bearing a terminal formyl moiety was readily prepared from
allyl alcohol 3s in 86% yield with 98% ee (eqn (3), right).
Moreover, the diastereoselective epoxidation of allyl alcohol
3s with m-CPBA was examined (eqn (3), left).22 Fortunately,
syn-epoxide 8, which is a key intermediate in the synthesis of
optically active 1,3-diols with three consecutive chiral carbon
centers,23 was obtained with a diastereomeric ratio of 76 : 24
with 97% ee (syn).
86%,
90% ee
96%,
90% ee
3m
3n
3o
>99%,
96% ee
94%,
84% ee
4
98%,
>99% ee
75%,
82% ee
5a
6b
14b,c
77%
3p [36%]a,
>99% ee
97%,
97% ee
3g
15c
76%,
(dr 55/45)
94% ee/
95% ee
45%
80%,
3q
7
8
3h
16b,c
99% ee
[15%]a,
85%
3r
ð2Þ
ð3Þ
3i (dr 59/41)17c
98% ee/
96% ee
99% ee
88%
3s [42%]a,
98% ee
56%,
96% ee
9
3j
18c
a
b
10 mol% of ligand 1b was used in place of 1a. Temperature was
c
0 1C. Toluene (2.5 M) was used as a solvent.
Finally, the 21-alkylation of ketones in place of aldehydes
was examined (Table 3).24 Unfortunately, both isopropylation
and cyclohexylation of acetophenone (9a) did not provide the
desired products, and the mixture of undesired aldol product
(11) and aldol condensation product (12) was obtained (entries
1 and 2). In sharp contrast, the isopropylation of 40-(trifluoro-
methyl)acetophenone (9b) and 30,50-bis(trifluoromethyl)aceto-
phenone (9c) proceeded without aldol formation at 0 1C for
24 h in the presence of 10 mol% of ligand 1a, and the desired
tertiary alcohols (10c and 10d) were obtained in moderate
yield with >99% ee (entries 3 and 4). Furthermore, the
cyclohexylation of 9b and 9c in the presence of 20 mol% of
ligand 1a provided the desired products 10e and 10f in
moderate to good yield with >99% ee (entries 5 and 6). To
the best of our knowledge, this is the first example of catalytic
asymmetric tertiary alcohol synthesis via di(21-alkyl)zinc addi-
tion to ketones.25
the first time, and the desired products were obtained with
a low diastereomeric ratio (ca. 6 : 4) but with high enantio-
selectivities (94–98% ee) (entries 7 and 8). Next, as an un-
precedented cyclic 21-alkyl addition to aldehydes, the addition
of (c-C5H9)2Zn and (c-C6H11)2Zn14 was explored. Fortunately,
the desired products were obtained with high enantioselectivities
from aromatic aldehydes (entries 11 and 12), heteroaromatic
aldehydes (entries 9 and 13), cycloaliphatic aldehydes (entries 10
and 15), a b-branched aliphatic aldehyde (entry 14), an a-branched
aliphatic aldehyde (entry 16), and a,b-unsaturated aldehydes
(entries 17 and 18). Less bulky 1b was often less effective than
more bulky 1a8 due to reduction byproducts, especially when
less-reactive aliphatic aldehydes were used (entries 8, 15, and
18). Some of the secondary alcohols (3, R0RCHOH) which
have two similar cyclic and/or acyclic fragments (R0 and R)
can hardly be obtained via complementary methods such as
asymmetric reduction of the corresponding ketones.15 In
this catalysis, optically active novel secondary alcohols with
similar R0 and R were successfully obtained in high yields with
high to excellent enantioselectivities (96–>99% ee).
In summary, we have developed a highly practical, catalytic
enantioselective 21-alkyl addition to aldehydes and ketones
with salt-free di(21-alkyl)zinc reagents. In this catalysis,
refined Charette’s reaction conditions using the molar ratio
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Table 3 Enantioselective 21-alkyl addition to ketonesa
Entry
1a (mol %)
Product
Yield and ee of 10
Yield of 11 and 12
Recovery of 9
1a
2b
3a
4a
5b
6b
10
20
10
10
20
20
10a
10b
10c
10d
10e
10f
(Ar = Ph, R = i-Pr)
(Ar = Ph, R = c-Hex)
(Ar = 4-CF3C6H4, R = i-Pr)
(Ar = 3,5-(CF3)2C6H3, R = i-Pr)
(Ar = 4-CF3C6H4, R = c-Hex)
(Ar = 3,5-(CF3)2C6H3, R = c-Hex)
0
0
84% (11a/12a = 2 : 3)
85% (11b/12b = 1 : 1)
o3%
o3%
o3%
o3%
15%
14%
59%
57%
57%
41%
38%, >99% ee
40%, >99% ee
40%, >99% ee
56%, >99% ee
a
b
Reaction was examined under solvent-free conditions. Reaction was examined under 2.5 M toluene conditions.
of 1/2.5/1.6 of ZnCl2/NaOMe/RMgCl in the presence of chiral
ligand 1 was essential. Moreover, solvent-free conditions
were critical for minimizing undesired reduction byproducts.
Optically active novel secondary alcohols could be transformed
to synthetically useful g-hydroxy-b-pyrone, a-alkoxy carboxylic
acid, a-hydroxy ketone, and 2,3-epoxyalcohol.
Financial support was provided by JSPS. KAKENHI
(20245022), MEXT. KAKENHI (21750094, 21200033), and
the Global COE Program of MEXT. We are grateful to Tosoh
Finechem Corp. for providing organometallic reagents.
J., 2008, 14, 10560; (c) Y. Muramatsu, S. Kanehira, M. Tanigawa,
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´
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´
9 Cote and Charette used a slight excess of Zn(OMe)2 (2–2.5 equiv.)
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14 Since (c-C6H11)2Zn is viscous at room temperature, toluene (2.5 M)
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ꢁc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 5443–5445 | 5445