Enantioselective alkynylation of a prochiral ketone catalyzed by C2-symmetric diamino diols

Article abstract of DOI:10.1016/S0040-4039(02)00444-6

C₂-Symmetric diamino diols were used as chiral ligands to induce the asymmetric addition of lithium acetylides to carbonyl groups. The enantiomeric excesses (up to 99% ee) depended on the structure of the acetylene.

Full text of DOI:10.1016/S0040-4039(02)00444-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2975–2977
Enantioselective alkynylation of a prochiral ketone catalyzed by
C -symmetric diamino diols
2
Biao Jiang* and Yan Feng
The State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fengling Road, Shanghai 200032, PR China
Received 3 January 2002; revised 20 February 2002; accepted 28 February 2002
Abstract—C -Symmetric diamino diols were used as chiral ligands to induce the asymmetric addition of lithium acetylides to
2
carbonyl groups. The enantiomeric excesses (up to 99% ee) depended on the structure of the acetylene. © 2002 Elsevier Science
Ltd. All rights reserved.
The asymmetric nucleophilic alkynylation of carbonyl
compounds is of considerable synthetic and industrial
importance. A new class of potent non-nucleoside
best of our knowledge, only ephedrine derivatives have
been successfully used as chiral ligands to promote
enantioselection in the addition of metal alkynylides to
aldehydes or ketones.
1
reverse transcriptase inhibitors was recently reported by
Merck Research Laboratories, and 1,4-dihydro-2H-3,1-
benoxazin-2-ones (efavirenz) have been approved by
2
the FDA for the treatment of AIDS. The key asym-
metric bond-forming step is the use of a lithiated
ephedrine to mediate acetylide addition to a tri-
3
fluoromethyl ketone. Great progress has been made
with the enantioselective alkynylation of aldehydes
4
using chiral amino alcohols as ligands. In contrast,
enantioselective nucleophilic alkynylation of prochiral
ketones has enjoyed only very limited success. To the
OH
N
OH
N
N
OH
N
OH
1
2
R
O
Cl
Ligand 1 or 2
n-BuLi
F3C
CF3
Cl
+
R
H
OH
NHR'
NHR'
3
4
5
R' = p-MeOC H CH
2
6
4
Scheme 1.
Keywords: alkynylation; enantioselective; C -symmetric diamino diol; ketone.
2
*
0
Corresponding author. E-mail: jiangb@pub.sioc.ac.cn
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00444-6

2
976
B. Jiang, Y. Feng / Tetrahedron Letters 43 (2002) 2975–2977
Table 1. Asymmetric addition of lithium acetylide to ketone 3
a
ee (%)b
20
Entry
R in 4
c-C H
Ligand
Yield of 5 (%)
[h]
D
1
2
3
4
5
6
1
2
1
1
1
1
80
78
82
78
75
75
99
42
75
53
49
11
+8.3
–
+22.4
+4.5
+40.3
+0.6
3
5
c-C H
3
5
Ph
n-C H
4
9
TBDMSOCH2
t-Butyl
a
Isolated yield.
b
Determined by Chiral HPLC on Chiralpak AD column eluted with hexane:isopropanol 7:3.
O
OH
Ligand 1
H
+
R
H
R
n-BuLi
6
4
7
Yield
ee
R= c-C H ,
85%
82%
84%
84%
80%
15%.
30%.
21%
99%
53%
3
5
Ph
n-C H
4
9
TBDMSOCH2
t-C H
4
9
Scheme 2.
In the course of our studies in the field of asymmetric
Extension of this reaction to the nucleophilic addition
of lithium acetylides to benzaldehyde gave the opposite
results (Scheme 2). When nucleophilic addition was
carried out by reacting lithium cyclopropylacetylide
with benzaldehyde in the presence of ligand 1, the
product was isolated with poor enantioselectivity (15%
ee). On the other hand, when the bulky lithium t-
butyldimethylsilyloxymethyl acetylide was used, high
enantioselectivity was obtained (99% ee).
synthesis, we have developed a new family of C -sym-
2
metric diamino diols 1 and 2 which have proved to be
good ligands in the enantioselective nucleophilic addi-
5
tion of diethylzinc to aldehydes and in asymmetric
6
allylic substitution. To probe further the potential of
this family in asymmetric reactions, we report here the
asymmetric alkynylation of aryl trifluoromethyl ketones
with lithium acetylides in the presence of C -symmetric
2
diamino diols (Scheme 1).
In summary, we have demonstrated the utility of C2-
symmetric diamino diol 1 as a chiral ligand for the
asymmetric addition of lithium acetylides to aryl trifl-
uoromethyl ketone and benzaldehyde. The enantiose-
lectivity of the alkynylation catalyzed by the
A preliminary study of the reaction was aimed at
determining the capacity for enantioselective alkynyla-
tion using 1 and 2 as chiral promoters. We found that
when the nucleophilic addition of lithium cyclopropyl-
acetylide (2 equiv.) to trifluoromethyl ketone 3 was
carried out in toluene in the presence of ligand 1 (1
equiv.), the acetylene 5 was obtained in an excellent
enantiomeric excess (99%) (Table 1, entry 1) and in
high chemical yield, while the use of 2 as a ligand gave
C -symmetric diamino diol 1 depends on the structure
2
of the acetylene. Up to 99% ee was obtained in the
nucleophilic addition of lithium cyclopropylacetylide
with trifluoromethyl ketones.
7
Acknowledgements
poor enantioselectivity (42% ee) (Table 1, entry 2). The
results with various lithium acetylides in the asymmetric
addition are summarized in Table 1. The results show
that the enantiomeric excess of the reaction depends on
the structure of the acetylene: lithium phenylacetylide
gave a product of 75% ee (Table 1, entry 3), while
lithium n-butyl acetylide, lithium t-butyldimethylsilyl-
oxymethyl acetylide and lithium t-butyl acetylide gave
the corresponding propargylic alcohols with low enan-
tioselectivity (Table 1, entries 4–6).
This research was supported by a Shanghai Overseas
Scholarship and by the National Natural Scientific
Foundation of China.
References
1. Frantz, D. E.; F a¨ ssler, R.; Tomooka, C. S.; Carreira, E.
M. Acc. Chem. Res. 2000, 33, 373.

B. Jiang, Y. Feng / Tetrahedron Letters 43 (2002) 2975–2977
2977
2
. Corbett, J. W.; Ko, S. S.; Rodgers, J. D.; Jeffrey, S.;
Bacheler, L. T.; Klabe, R. M.; Diamond, S.; Lai, C.-M.;
Rabel, S. R.; Saye, J. A.; Adams, S. P.; Trainor, G. L.;
Anderson, P. S.; Erickson-Viitanen, S. K. Antimicrob.
Agents Chemother. 1999, 43, 2893.
. (a) Thompson, A. S.; Corley, E. G.; Huntington, M. F.;
Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 8937; (b)
Thompson, A. S.; Corley, E. G.; Huntington, M. F.;
Grabowski, E. J. J.; Remenar, J. F.; Collum, D. B. J. Am.
Chem. Soc. 1998, 120, 2038; (c) Li, Z.; Upadhyay, V.;
DeCamp, A. E.; DiMichele, L.; Reider, P. J. Synthesis 1999,
6. Zhang, A.; Jiang, B.; Feng, Y. Tetrahedron: Asymmetry
2000, 11, 3123.
7. All of the compounds gave satisfactory spectroscopic data:
Representative experimental procedure: Under argon, to a
solution of compound 1 (178 mg, 0.5 mmol) in THF (2 mL)
was added cyclopropylacetylene (0.09 mL, 1 mmol) at
3
−
20°C, and this was followed by the addition of a solution
of n-BuLi in hexanes (2.5 M, 0.8 mL, 2 mmol). The mixture
was then warmed to 0°C and then cooled to −70°C. A
solution of trifluoromethyl aryl ketone 3 (172 mg, 0.5 mmol)
in THF (10 mL) was added. The resulting red solution was
stirred for 2 h and then quenched by the addition of 2N HCl
1
453; (d) Tan, L.; Chen, C.; Tillyer, R. D.; Grabowski, E.
J. J.; Reider, P. J. Angew. Chem., Int. Ed. Engl. 1999, 38,
11.
(
5 mL). The reaction mixture was extracted with ethyl
7
acetate (3×20 mL). The combined extracts were washed with
brine and dried with sodium sulfate. After the solvent was
removed in vacuo, the residue was purified by flash chro-
4
. (a) Soai, K.; Niwa, S. Chem. Lett. 1989, 4812; (b) Niwa, S.;
Soai, K. J. Chem. Soc., Perkin Trans. 1990, 1, 937; (c) Ramos
Tombo, G. M.; Didier, E.; Loubinoux, B. Synlett 1990, 547;
matography (eluent:hexane:ethyl acetate=8:1, R =0.6) to
(
d) Frantz, D. E.; F a¨ ssler, R.; Carreira, E. M. J. Am. Chem.
f
give 5 as a yellow solid (120 mg, 80% yield). The product
was shown to have 99% ee by chiral HPLC (Chiralpak AD
column eluted with hexane:isopropanol 7:3).
Soc. 2000, 122, 1806; (e) Boyal, J.; Lopez, F.; Sasaki, H.;
Frantz, D. E.; Carreira, E. M. Org. Lett. 2000, 2, 4233.
. Jiang, B.; Feng, Y. Tetrahedron: Asymmetry 2001, 12, 2323.
5