Enantio- and diastereoselective Ir-catalyzed allylic substitutions for asymmetric synthesis of amino acid derivatives

Article abstract of DOI:10.1002/anie.200250654

Simply switching the base employed in the first enantioselective allylic substitutions of diphenylimino glycinate 1 with 2, which are catalyzed by an Ir complex of chiral phosphite 5, allows the two branched diastereomers 3 and 4 to be selectively synthes

Full text of DOI:10.1002/anie.200250654

Communications
Enantioselective Allylation
occurs at the more substituted terminus with high regio-,
diastereo-, and enantioselectivity.[8] However, there are no
reports concerning the asymmetric synthesis of both diaster-
eomers D and E as major products from the same starting
materials and the same chiral ligand. We report here the first
enantioselective allylic substitutions of 1 catalyzed by an
iridium complex of chiral phosphite 10, and the diastereose-
lective synthesis of the products 4 and 5 by simply switching
the base employed (Scheme 2).
Enantio- and Diastereoselective Ir-Catalyzed
Allylic Substitutions for Asymmetric Synthesis of
Amino Acid Derivatives**
Takatoshi Kanayama, Kazumasa Yoshida,
Hideto Miyabe, and Yoshiji Takemoto*
Transition-metal-catalyzed asymmetric allylic substitution is a
useful reaction in organic synthesis.[1] In the reaction with
symmetric C nucleophiles such as dialkyl malonates, good
yields and high enantioselectivities can now be obtained with
an appropriate combination of a transition metal and a chiral
ligand.[2–5] In contrast to the symmetric C nucleophiles, allylic
substitution of 3-substituted allylic alcohols B with unsym-
metrical C nucleophiles A is a tough and challenging task,
because regio-, diastereo-, and enantioselectivities must be
controlled (Scheme 1). In the last few years, research has
Scheme 2. Ir-catalyzed asymmetric allylic substitution of 1 with 2a,a’.
Our previous work prompted us to examine PTC 6 as a
chiral catalyst in Ir-catalyzed allylic substitutions (Table 1).
We first carried out the Ir-catalyzed reaction of 1 and
benzoate 2a in the presence of the chiral PTC 6, 50%
KOH, [{IrCl(cod)}2] (cod = cyclooctadiene), and (PhO)3P
Table 1: Ir-catalyzed asymmetric allylic substitution of 1 and 2a,a’ with
chiral PTC 6 or various chiral ligands 7–10.[a]
Scheme 1. Transition-metal-mediated asymmetric allylic substitution.
Entry Substrate Ligand (mol%)
Yield [%][b] (4:5) ee of 4 [%][c]
1
2
3
4
5
6[e]
7[e]
2a
2a
2a
2a
2a
2a’
2a’
6 (10), (PhO)3P (40) 40 (75:25)
46
focused on finding catalysts and chiral ligands that favor the
formation of branched chiral products D and E in the allylic
substitution of a-amino esters A with B.[6,7] We have already
reported Pd-mediated asymmetric allylic alkylation of diphe-
nylimino glycinate 1 with several allylic acetates in the
presence of the chiral phase-transfer catalyst (PTC) 6 to give
the chiral products C with high enantioselectivity (up to
97% ee).[6a] In contrast to the palladium catalyst, some
transition metals, such as Ir,[3] Mo,[4] and W,[5] promote allylic
alkylation at the more highly substituted terminus of the
allylic substrate. Trost et al. recently reported that Mo-
catalyzed asymmetric allylic alkylation with azlactones
(R)-7 (20)
(S)-8 (40)
(R)-9 (20)
(R)-10 (20)
(R)-9 (20)
(R)-10 (20)
29 (69:31)
7 (86:14)
6 (67:33)
11 (73:27)
0
32[d]
68[d]
95
93
–
97
82 (82:18)
[a] All reactions were carried out in toluene. The ratio of 1:2:50%
KOH:[{IrCl(cod)}2] was 100:100:300:10 unless otherwise noted.
[b] Yields of isolated products. [c] Determined by HPLC analysis with
Daicel Chiral Pack OD-H column. [d] The enantiomer of 4 was obtained.
[e] The reaction was carried out at 08C.
(entry 1). The reaction was complete after 8 h at room
temperature and gave the branched products 4a and 5a as
major products (40% yield, 4a:5a = 75:25) but with low
enantioselectivity (46% ee). We next examined the effect of
chiral ligands 7–10[9] in place of chiral PTC 6 on the
enantioselectivity. The reaction of 1 with 2a was carried out
in the presence of 50% KOH (3 equiv), [{IrCl(cod)}2]
(10 mol%), and chiral phosphites (20–40 mol%). In all
cases, no linear product could be detected. Indeed, the
[*] Prof. Dr. Y. Takemoto, T. Kanayama, K. Yoshida, Dr. H. Miyabe
Graduate School of Pharmaceutical Sciences
Kyoto University
Sakyo-ku, Kyoto 606-8501 (Japan)
Fax: (+81)75-753-4569
E-mail: takemoto@pharm.kyoto-u.ac.jp
[**] This research was supported by grants from the Japan Health
Sciences Foundation and Grant-in-Aid for Scientific Research (C)
from the Ministry of Education, Science, Sports, and Culture, Japan.
2054
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DOI: 10.1002/anie.200250654
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Angewandte
Chemie
Table 3: Ir-catalyzed allylic substitution of 1 with various substrates
2b–f.
enantioselectivity was dramatically affected by the substitu-
ent R of the ligands. Whereas addition of the known chiral
phosphites 7[3a] and 8[9f] in place of (PhO)3P gave the branched
product 4a as a major product with moderate enantioselec-
tivity, the new ligands 9 and 10 gave 4a in 95 and 93% ee,
respectively, albeit at the expense of chemical yield
(entries 2–5). However, hydrolysis of 2a to cinnamyl alcohol
predominantly occurred under these conditions. We next used
phosphate 2a’ as an allylic substrate which should be resistant
to hydrolysis. After several experiments, it was revealed that
the best result (82% yield, 4a:5a = 82:18, 97% ee) was
obtained when the reaction was performed at 08C with
phosphate 2a’ (entries 6 and 7). Furthermore, use of the
bidentate chiral ligand 10, which promoted the reaction at
08C, was essential to improve both the chemical yield and
stereoselectivity of 4.
Entry Substrate Method[a]
Yield [%][b]
branched linear (4:5)
Ratio
ee [%][c]
4
2
5
1
2
3
4
5[d]
6
7
8
2b
2c
2d
2e
2 f
2b
2c
2d
2e
2 f
A
A
A
A
A
B
B
B
B
B
77
77
79
97
63
82
78
81
84
88
0
0
0
0
0
0
0
<1
<1
78:22 97 63
68:32 97 68
76:24 97 74
77:23 94 69
83:17 91 74
13:87 59 85
10:90 93 94
10:90 73 94
11:89 67 96
9
10
1.1 34:66 51 70
[a] Method A: In toluene at 08C unless otherwise noted. The ratio of
1:2:50% KOH:[{IrCl(cod)}2]:(R)-10 was 100:100:300:10:20. Method B:
In THF at 08C. The ratio of 1:2:LiN(SiMe3)2:[{IrCl(cod)}2]:(R)-10 was
150:100:150:10:20. [b] Yields of isolated products. [c] Determined by
HPLC analysis with a Daicel Chiral Pack OD-H column. [d] The reaction
was carried out at room temperature.
Having established higher enantioselectivity, we explored
the effect of the countercations of the enolate with 2a’ and 10,
and the results are shown in Table 2. It is noteworthy that the
Table 2: Ir-catalyzed allylic substitution of 1 and 2a’ under various
reaction conditions.[a]
Entry Reaction conditions
Yield [%][b]
branched linear (4:5)
Ratio
ee[%][c]
4
5
1
2
3
4
5
6
7
CsOH·H2O, toluene 43
0
0
0
0
23
3
70:30 95
59
66
72
73
63
96
92
50% KOH, toluene
KN(SiMe3)2, THF
NaH, THF
82
28
29
20
56
82
82:18 97
79:21 48
62:38 91
LiBr, DBU[d], THF
LDA, THF
30:70 44
[e]
11:89
–
LiN(SiMe3)2, THF
<1
12:88 56
Scheme 3. Ir-catalyzed reaction of 1 with various allylic substrates
2b–f.
[a] All reactions were carried out at 08C in the presence of [{IrCl(cod)}2]
(10 mol%) and (R)-10 (20 mol%). [b] Yields of isolated products.
[c] Determined by HPLC analysis with Daicel Chiral Pack OD-H column.
[d] DBU=1,8-diazabicyclo[5.4.0]undec-7-ene. [e] The ee was not deter-
mined.
(> 94% ee). Similarly, by using method B, other branched
products 5b–e could be synthesized stereoselectively (4:5 =
13:87–10:90, 85–96% ee). In contrast, due to lower reactivity
of the methyl carbonate, the Ir-catalyzed allylic substitution of
2 f required prolonged reaction time and elevated temper-
ature. As a result, the yield and stereoselectivity of the
branched products 4 f and 5 f become somewhat lower than
those of 4a–e and 5a–e. In any event, these two protocols are
applicable to several allylic substrates and are demonstrated
to be a versatile tool for asymmetric synthesis of both
diastereomers 4a–f and 5a–f.
The relative and absolute configurations of products 4a
and 5a were determined by comparison with the known
compounds.[7a] The configurations of 4b–f and 5b–f were then
assumed by analogy. From the results described above, the
stereochemical course of the reaction can be explained as
follows. Initially, the p- or s-allyl complex F is formed by
attack of the iridium(i) complex of the ligand on the allylic
substrate 2. The nucleophilic attack of the enolate of 1 at the
allylic carbon atom trans to the phosphorus atom would give
the chiral products 4 and 5 with high enantioselectivity.
Although we cannot explain the different behavior of the
bases at this stage, it might be attributable to the geometry of
the enolate of 1. It was assumed that the use of KOH as a base
would give predominantly the E enolate G, whereas the Z
countercations had a more significant influence on the
diastereoselectivity (4a/5a) than on the enantioselectivity
for 4a. In addition, for diastereoselective synthesis of 4a, the
reaction of 1 and 2a’ with 50% KOH in toluene (method A)
was superior to reactions involving KN(SiMe3)2, CsOH, and
NaH (entries 1–4), whereas these bases gave 4a as a major
product with more than 90% ee. On the other hand, use of
lithium bases tends to produce the other diastereomer 5a as a
major product (entries 5–7). Among them, LiN(SiMe3)2 was
the best base in terms of chemical yield and stereoselectivity
(82% yield, 4a:5a = 12:88, 92% ee; method B). These two
methods allow us to synthesize both diastereomers 4a and 5a
with high enantioselectivity.
Methods A and B were examined for various allylic
substrates 2b–f (Table 3, Scheme 3). Since the phosphate of p-
methylcinnamyl alcohol could not be prepared, we employed
methyl carbonate 2 f as substrate. In general, the Ir-catalyzed
allylic substitution was not affected by the para and meta
substituents of the aromatic ring of 2b–e. Thus, method A
gave the corresponding branched products 4b–e diastereose-
lectively (4:5 = 68:32–78:22) with excellent enantioselectivity
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enolate H would be formed with LiN(SiMe3)2 as base
(Figure 1).[10]
In conclusion, we have developed the first enantioselec-
tive Ir-catalyzed allylic substitutions of diphenylimino glyci-
nate 1 by using chiral bidentate ligand 10 (up to 97% ee), and
also succeeded in the diastereoselective asymmetric synthesis
of both diastereomers 4 and 5 by simply switching the base
employed. The influence of the base on diastereoselectivity
and further applications of this asymmetric allylic substitution
are currently under investigation.
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Figure 1. The plausible allyl IrIII complex F.
Experimental Section
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General procedure for asymmetric allylic substitution: Method A: A
50% KOH solution (38 mL, 0.51 mmol) was added to a stirred
solution of tert-butyl glycinate benzophenone imine (1; 50 mg,
0.17 mmol), diethyl phosphate 2a’ (46 mg, 0.17 mmol), [{IrCl(cod)}2]
(11 mg, 0.017 mmol), and (R)-10 (14 mg, 0.034 mmol) in dry toluene
(1.4 mL) at 08C under an argon atmosphere, and the resulting
mixture was stirred vigorously at 08C for 20 h. The suspension was
diluted with diethyl ether (15 mL), and the organic phase was washed
with a saturated aqueous soltion of NaHCO3 (2 mL) and brine (2 mL)
and then dried over Na2SO4. After evaporation of the solvent, the
crude product was purified by column chromatography (basic silica
gel, AcOEt/hexane 1/500) to give the desired products 4a (46 mg,
67%) and 5a (11 mg, 15%) as a colorless oil.
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Method B: A solution of 1 (75 mg, 0.25 mmol) in dry THF (1 mL)
was added to a stirred solution of LiN(SiMe3)2 (0.25 mmol) in THF
(0.16 mL) at À788C. After being stirred for 30 min, the mixture was
slowly added to a stirred solution of 2a’ (46 mg, 0.17 mmol),
[{IrCl(cod)}2] (11 mg, 0.017 mmol), and (R)-10 (14 mg, 0.034 mmol)
in dry THF (0.4 mL) at 08C under an argon atmosphere. After
completion of the addition (30 min), the resulting mixture was
quenched with water (2 mL) and diethyl ether (40 mL). The organic
phase was washed with brine (2 mL) and then dried over Na2SO4.
After evaporation of the solvent, the crude product was purified by
column chromatography (basic silica gel, AcOEt/hexane 1/500) to
give 4a (7.0 mg, 10%) and 5a (50 mg, 72%).
The enantioselectivity was determined by chiral HPLC (Daicel
Chiralpak OD-H, iPrOH/hexanes 0.6/99.4, flow rate 0.3 mLminÀ1
,
l = 254 nm, retention times: 4a (major) 26.5 min, (minor) 23.8 min,
5a (major) 27.4 min, (minor) 25.7 min).
Received: November 28, 2002
Revised: February 13, 2003 [Z50654]
Keywords: allylation · amino acids · enantioselectivity · iridium ·
.
P ligands
2056
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Angew. Chem. Int. Ed. 2003, 42, 2054 – 2056