Catalytic asymmetric addition of terminal alkynes to aldehydes mediated by (1R,2R)-2-(dimethylamino)-1,2-diphenylethanol

Article abstract of DOI:10.1002/adsc.200505157

Catalytic asymmetric alkynylation of aldehydes with terminal alkynes was catalyzed by zinc triflate and (1R,2R)-2-(dimethylamino)-1,2-diphenylethanol in toluene to give the corresponding alcohols with high enantiomeric excess up to 98% in good yields.

Full text of DOI:10.1002/adsc.200505157

FULL PAPERS
DOI: 10.1002/adsc.200505157
Catalytic Asymmetric Addition of Terminal Alkynes to
Aldehydes Mediated by (1R,2R)-2-(Dimethylamino)-
1,2-diphenylethanol
Mitsuaki Yamashita, Ken-ichi Yamada, Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Fax: (þ81)-75-753-4604, e-mail: tomioka@pharm.kyoto-u.ac.jp
Received: April 18, 2005; Accepted: July 11, 2005
Abstract: Catalytic asymmetric alkynylation of alde- Keywords: alcohols; aldehydes; alkynes; asymmetric
hydes with terminal alkynes was catalyzed by zinc tri- catalysis; zinc
flate and (1R,2R)-2-(dimethylamino)-1,2-diphenyletha-
nol in toluene to give the corresponding alcohols with
high enantiomeric excess up to 98% in good yields.
Introduction
shown in 2 would not exist. This expectation came
from our previous studies on the external chiral li-
The catalytic asymmetric alkylation of aldehydes with gand-controlled asymmetric reactions where 5-mem-
dialkylzinc reagents constitutes one of the significant bered chelation plays a pivotal role.[9] We describe here-
historical milestones of modern asymmetric reactions.[1] in that a chiral amino alcohol 3a (R¼Ph) mediated the
Headed by Oguni and Noyori, tremendous efforts have highly efficient catalytic asymmetric alkynylation of al-
been devoted to the development of efficient chiral dehydes with terminal alkynes giving adducts with up
sources.[2] Chiral amino alcohols have become the estab- to 98% ee.
lished sources for this purpose. The stereochemical
pathway of the chiral amino alcohol-mediated asym-
metric reaction has been well established by proposing
a bimetallic complex of a chiral zinc alkoxide and a dio-
rganozinc species, which also rationalizes the enhanced
reactivity of the diorganozinc reagent. However, the
drawback of this asymmetric alkylation exists in the rel-
atively poor availability and necessity of careful han-
dling of diorganozinc reagents, although many protocols
for their preparation have been reported. Recent focus
Figure 1. Chiral amino alcohols 1 and 3, and their complexes
2 and 4 with organozinc species.
has been adjusted to the alkynylation of aldehydes
with terminal alkynes, mostly because slightly acidic ter-
minal alkynes are readily convertible in situ to zinc ace-
Results and Discussion
tylides.[3] These brilliant asymmetric alkynylations of al-
dehydes and ketones have used the same type of chiral
amino alcohols as depicted by 1 as a chiral source (Fig-
ure 1).[4] These amino alcohols have been proposed to
Asymmetric Alkynylation of Aldehydes
form a bimetallic chelated complex 2[2b,5] that gave the The alkynylation of cyclohexanecarbaldehyde (5a; R1 ¼
adducts with the observed absolute configurations.[6,7] c-Hex) with phenylacetylene (6a; R2 ¼Ph) was conduct-
However, one exception using a chiral amino alcohol ed in the presence of 0.22 equivs. of (1R,2R)-2-(dimethyl-
3, instead of 1 has been reported where the adducts amino)-1,2-diphenylethanol (3a; R¼Ph), 0.2 equivs. of
were obtained in high enantioselectivity even with ke- zinc triflate and 0.5 equivs. of triethylamine in toluene,
tones.[8] We are also interested in the amino alcohol of that is, under the conditions developed by Carreira
type 3 because of the expected relatively higher stability with use of the chiral amino alcohol 1a (R¼Me, Ph)
of the bimetallic complex 4, where the steric repulsion (Scheme 1).[4 g] The reaction proceeded quite smoothly
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Mitsuaki Yamashita et al.
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of 3a, 0.55 equivs. of zinc triflate and 0.6 equivs. of tri-
ethylamine at room temperature for 12 h to give 7ca
with 98% ee in 75% yield (entry 8). The reaction of 5c
with 6b at room temperature for 12 h gave 7cb with
98% ee in 47% yield, along with recovery of 5c in 43%
yield (entry 9).
Stereochemical Pathway
Scheme 1. Chiral amino alcohol 3a-mediated catalytic asym-
metric alkynylation of 5 with 6.
The chiral amino alcohol 3a-mediated alkynylation of 5a
(R1 ¼c-Hex) with 6a (R2 ¼Ph) produced (S)-7aa. The
absoluteconfiguration ofthe newly created chiralcenter
at room temperature (rt) for 2 h to give the alcohol (S)- is predictable based on the model 8 (Figure 2). The car-
7aa[10] in 96% isolated yield (Table 1, entry 1). The enan- bonyl oxygen atom of the aldehyde coordinates to the
tiomeric excess (ee) was determined to be 96% by chiral zinc of the bimetallic complex, and an alkynyl group at-
stationary phase HPLC. This result encouraged us to tacks the carbonyl carbon of the aldehyde as shown to
continue our examination on other alkynes and alde- produce the alcohol (S)-7aa with the same absolute con-
hydes, because the yield and enantioselectivity are high- figuration.
er than those (94% yield, 86% ee) obtained by using chi-
ral amino alcohol 1a (R¼Me, Ph).[4g] Thus, the reaction
of 5a with phenylethylacetylene (6b; R2 ¼PhCH2CH2)
at room temperature for 5 h gave 7ab with 93% ee quan-
titatively (entry 2). The reaction with triethylsilylacety-
lene (6c; R2 ¼Et3Si) at 508C for 6 h gave 7ac with 98% ee
in 79% yield (entry 3). These results apparently indicate
that the chiral amino alcohol 3a is superior or equal to 1a
in yield and enantioselectivity.
Figure 2. Model 8 predicting the stereochemistry of (S)-7.
The reaction of benzaldehyde (5b; R1 ¼Ph) with 6a re-
quired relatively harsh conditions, at 508C for 24 h, to
give 7ba with 93% ee in 51% yield, along with recovery
of 5c in 45% yield (entry 4).[11] With use of 0.6 equivs. of
3a, 0.55 equivs. of zinc triflate and 0.6 equivs. of triethyl- Conclusion
amine the reaction proceeded at room temperature for
12 h to give 7ba with 94% ee in 80% yield (entry 5). Based on the expectation that a chiral amino alcohol 3
The reaction with 6b at room temperature for 12 h should form a relatively more rigid 5-membered chelate
gave 7bb with 96% ee in 73% yield (entry 6). The reac- with organozinc reagent than 1 where two contiguous
tion of 5b with 6c at 1008C for 12 h gave 7bc with 90% ee substituents are cis, the highly efficient alkynylation of
in 30% yield along with concomitant formation of its ke- aldehydes with terminal alkynes was developed by using
tone and benzyl alcohol each in 19% yield (entry 7).
3a as a chiral amino alcohol. The enantioselectivity,
1
¼
Cinnamaldehyde (5c; R ¼PhCH CH) was also an mediated by 3a, reached up to 98% and was thus higher
applicable substrate under the conditions of 0.6 equivs. than those observed by using 1a.
Table 1. Catalytic asymmetric alkynylation of aldehydes 5 with 6 by the mediation of 3a.
Entry
R1
R2
Temperature [ 8C]
Time [h]
Yield [%]
ee [%]
1
2
3
4
c-Hex
c-Hex
c-Hex
Ph
Ph
Ph
Ph
rt
rt
50
50
rt
rt
100
rt
1
5
6
24
12
12
12
12
12
96
99
79
51
80
73
30
75
47
96
93
98
93
94
96
90
98
98
Ph(CH2)2
Et3Si
Ph
5[a]
6[a]
7
Ph
Ph(CH2)2
Et3Si
Ph
Ph
8[a]
9[a]
PhCH CH
PhCH CH
¼
¼
Ph(CH2)2
rt
[a]
0.6 equivs. of amino alcohol 3a, 0.55 equivs. of Zn(OTf)2, and 0.6 equivs. of Et3N were used.
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Catalytic Asymmetric Addition of Terminal Alkynes to Aldehydes
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Experimental Section
(S)-1,3-Diphenylprop-2-yn-1-ol (7ba; R1 ¼Ph,
R2 ¼Ph;[13] Entry 5)
All melting points are uncorrected. IR spectra were expressed
1
in cmꢀ1. H and 13C NMR spectra were measured in CDCl3.
0.55 equivs. of Zn(OTf)2 (200 mg, 0.55 mmol), 0.6 equivs. of
amino alcohol 3a (145 mg, 0.60 mmol), and 0.6 equivs. of tri-
ethylamine (84 mL, 0.60 mmol) were used. A colorless oil
(yield: 167 mg, 80%) was obtained by column chromatography
(hexane/EtOAc, 8/1); Rf (hexane/EtOAc, 9/1): 0.11; [a]2D5:
ꢀ1.6 (c 0.88, CHCl3) for 94% ee (HPLC, Daicel Chiralcel
OD-H, hexane/2-PrOH, 9/1, 1.0 mL/min, 254 nm, minor
10.9 min and major 19.8min).
Chemical shift values are expressed in ppm relative to internal
tetramethylsilane. Abbreviations are as follows: s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet; br, broad. Column
chromatography was carried out on silica gel. The absolute
configuration of the product alcohols 7 was determined by
comparison of specific rotations and retention times on
HPLC with those reported, except for 7bc whose absolute con-
figuration was tentatively assigned by analogy. Zinc triflate, al-
dehydes and alkynes were purchased and purified by the stand-
ard methods prior to use. Chiral amino alcohol 3a was prepared
according to the reported procedure.[12]
(S)-1,5-Diphenylpent-2-yn-1-ol [7bb; R1 ¼Ph,
R2 ¼Rh(CH2)2;[13] Entry 6]
0.55 equivs. of Zn(OTf)2 (200 mg, 0.55 mmol), 0.6 equivs. of
amino alcohol 3a (145 mg, 0.60 mmol), and 0.6 equivs. of tri-
ethylamine (84 mL, 0.60 mmol) were used. A colorless oil was
obtained by column chromatography (hexane/EtOAc, 9/1);
yield: 173 mg (73%); Rf (hexane/EtOAc, 6/1): 0.06; [a]2D9:
ꢀ15.1 (c 1.0, CHCl3) for 96% ee (HPLC, Daicel Chiralcel
OD-H, hexane/2-PrOH, 9/1, 1.0 mL/min, 254 nm, minor
16.0 min and major 26.9 min). The starting 5b was recovered
in 12% yield.
Typical Procedure for the Amino Alcohol 3a-
Mediated Catalytic Asymmetric Addition of Alkynes
to Aldehydes;(S)-1-Cyclohexyl-3-phenylprop-2-yn-1-ol
(7aa;R1 ¼c-Hex, R2 ¼Ph; Table 1, entry 1)
Under an argon atmosphere, to a mixture of Zn(OTf)2 (73 mg,
0.20 mmol) and amino alcohol 3a (53 mg, 0.22 mmol) in tol-
uene (1.0 mL) was added triethylamine (70 mL, 0.5 mmol)
and the mixture was stirred for 2 h at room temperature. Ethyn-
ylbenzene (6a; 0.13 mL, 1.2 mmol) was added and the solution
was stirred for additional 0.5 h. To the solution was added cy-
clohexanecarbaldehyde (5a; 0.11 mL, 1.0 mmol) in one por-
tion. The reaction mixture was stirred at room temperature
for 2 h. The mixture was quenched with saturated ammonium
chloride at room temperature and extracted with ethyl acetate.
The organic extracts were washed with brine, dried over so-
dium sulfate, and then concentrated to give a pale yellow oil
(290 mg). Column chromatography (hexane/EtOAc, 20/1)
gave 7aa[13] as acolorless oil; yield:206 mg (96% yield); Rf (hex-
ane/EtOAc, 9/1): 0.14; [a]2D6: þ10.9 (c 1.1, CHCl3) for 96% ee
(HPLC, Daicel Chiralcel OD-H, hexane/2-PrOH, 9/1,
1.0 mL/min, 254 nm, minor 5.0 min and major 10.4 min).
(S)-3-(Triethylsilyl)-1-phenylprop-2-yn-1-ol (7bc;
R1 ¼Ph, R2 ¼Et3Si; Entry 7)
The reaction was run at 1008C. A colorless was obtained oil by
column chromatography (hexane/EtOAc, 30/1); yield: 74 mg
(30%); Rf (hexane/EtOAc, 9/1): 0.23; [a]2D5: ꢀ22.2 (c 0.76,
CHCl3) for 90% ee (HPLC, Daicel Chiralcel OD-H, hexane/
2-PrOH, 100/6, 0.6 mL/min, 254 nm, major 17.7 min and minor
24.9 min); 1H NMR: d¼0.64 (6H, q, J¼7.8Hz), 1.01 (9H, t, J¼
7.8Hz), 2.14 (1H, d, J¼6.4 Hz), 5.48(1H, d, J¼6.4 Hz), 7.33
(1H, t, J¼7.2 Hz), 7.38(2H, dd, J¼7.0, 7.2 Hz), 7.57 (2H, d,
J¼7.0 Hz); 13C NMR: d¼4.2, 7.4, 65.1, 89.2, 106.2, 126.8,
128.4, 128.6, 140.5; IR (neat): n¼3348, 1454, 1415, 1385,
1042, 983, 729; EI-MS: m/z¼246 (Mþ), 175, 147, 115, 99;
anal. calcd. for C15H22OSi: C 73.11, H 9.00; found: C 73.20, H
8.90.
(S)-1-Cyclohexyl-5-phenylpent-2-yn-1-ol [7ab; R1 ¼c-
Hex, R2 ¼Ph(CH2)2;[13] Entry 2]
A colorless oil (yield: 240 mg, 99%) was obtained by column
chromatography (hexane/EtOAc, 15/1); Rf (hexane/EtOAc,
10/1): 0.25; [a]2D8: þ1.5 (c 1.0, CHCl3) for 93% ee (HPLC, Dai-
cel Chiralcel OD-H, hexane/2-PrOH, 9/1, 1.0 mL/min, 254 nm,
minor 9.7 min and major 13.2 min).
(S)-(E)-1,5-Diphenylpent-1-en-4-yn-3-ol (7ca;
1
2
[14]
¼
R ¼PhCH CH, R ¼Ph; Entry 8)
0.55 equivs. of Zn(OTf)2 (200 mg, 0.55 mmol), 0.6 equivs. of
amino alcohol 3a (145 mg, 0.60 mmol), and 0.6 equivs. of tri-
ethylamine (84 mL, 0.60 mmol) were used. Colorless needles
were obtained by column chromatography (hexane/EtOAc,
9/1); yield: 176 mg (75%); mp 88–898C; Rf (hexane/EtOAc,
9/1): 0.08; [a]2D5: ꢀ4.9 (c 1.0, CHCl3) for 98% ee (HPLC, Daicel
Chiralcel OD-H, hexane/2-PrOH, 9/1, 1.0 mL/min, 254 nm,
minor 22.7 min and major 66.3 min).
(S)-1-Cyclohexyl-3-(triethylsilyl)prop-2-yn-1-ol (7ac;
R1 ¼c-Hex, R2 ¼Et3Si;[4g] Entry 3)
The reaction was run at 508C. A colorless oil (yield: 198mg,
79%) was obtained by column chromatography (hexane/
EtOAc, 30/1); Rf (hexane/EtOAc, 9/1): 0.27; [a]2D7: þ5.2 (c
1.1, CHCl3) for 98% ee. The ee was determined after conver-
sion to 3,5-dinitrobenzoate (HPLC, Daicel Chiralcel OD-H,
hexane/2-PrOH, 100/6, 0.3 mL/min, 254 nm, minor 35.6 min
and major 38.1 min).
(S)-(E)-1,7-Diphenylhept-1-en-4-yn-3-ol [7cb;
R ¼PhCH CH, R ¼Ph(CH2)2; Entry 9]
0.55 equivs. of Zn(OTf)2 (200 mg, 0.55 mmol), 0.6 equivs. of
1
2
[13]
¼
amino alcohol 3a (145 mg, 0.60 mmol), and 0.6 equivs. of tri-
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Mitsuaki Yamashita et al.
FULL PAPERS
ethylamine(84 mL, 0.60 mmol) were used. Column chromatog-
raphy (hexane/EtOAc, 9/1) gave 7cb as colorless needles; yield:
123 mg (47%); mp 67–688C; Rf (hexane/EtOAc, 6/1): 0.06;
[a]2D3: ꢀ11.7 (c 1.1, CHCl3) for 98% ee (HPLC, Daicel Chiral-
cel OD-H, hexane/2-PrOH, 85/15, 1.0 mL/min, 254 nm, major
26.5 min and minor 34.8min). The starting 5c was recovered in
43% yield.
[5] J. Rudolph, T. Rasmussen, C. Bolm, P.-O. Norrby, An-
gew. Chem. Int. Ed. 2003, 42, 3002–3005.
[6] Reaction with sources having one chiral center: a) G.
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Acknowledgements
This research was partially supported by the 21st Century COE
(Center of Excellence) Program “Knowledge Information In-
frastructure for Genome Science” and a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
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Adv. Synth. Catal. 2005, 347, 1649 – 1652