Copper catalyzed asymmetric propargylation of aldehydes

Article abstract of DOI:10.1021/ja103312x

The highly enantio- and regioselective copper catalyzed asymmetric propargylation of aldehydes with a propargyl borolane reagent is reported. The methodology demonstrated broad functional group tolerance and provided high enantioselectivities for aliphatic, vinyl, and aryl aldehydes. The utility of the TMS homopropargylic alcohols was demonstrated by the facile conversion to a chiral dihydropyranone.

Full text of DOI:10.1021/ja103312x

Published on Web 05/18/2010
Copper Catalyzed Asymmetric Propargylation of Aldehydes
Daniel R. Fandrick,* Keith R. Fandrick, Jonathan T. Reeves, Zhulin Tan, Wenjun Tang,
Andrew G. Capacci, Sonia Rodriguez, Jinhua J. Song, Heewon Lee, Nathan K. Yee, and
Chris H. Senanayake
Chemical DeVelopment, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road/P.O. Box 368,
Ridgefield, Connecticut 06877-0368
Received April 19, 2010; E-mail: daniel.fandrick@boehringer-ingelheim.com
Table 1. Optimization of the Cu Catalyzed Propargylationa
Chiral homopropargylic alcohols are versatile and valuable
synthetic intermediates due to the alkyne functional group which
provides a convenient synthetic handle for coupling or derivation.1
The enantioselective propargylation of aldehydes with a chiral allene
reagent2 or intermediate3 has shown broad synthetic utility.
Propargylations utilizing a catalytic amount of a chiral source are
limited to a Barbier type addition,1d,e,4 or asymmetric Lewis acid
entry
Cu salt
ligand
conv.b
7:8.c
[ee]d
or base catalysis with a metalloallene reagent.5,6 Recently, we
reported the zinc catalyzed propargylation of aldehydes with a
propargyl borolane based on a B/Zn exchange mechanism.7
However, propargylations with allenyl-zinc species with chiral
amino-alcohol ligands were shown to proceed with only modest
enantioselectivity.8 Alternatively, if a copper alkoxide catalyst is
able to promote this mechanism, then a chiral phosphine ligand
could be utilized to effect asymmetric induction. Herein, we report
the discovery of a highly enantioselective and site selective copper
alkoxide catalyzed propargylation of aldehydes with a propargyl
borolane.
1e,f
2e
3
4
5
6
7
8
9
10
11g
12g
13g
14g
none
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
none
none
none
XANTPHOS
BINAP
iPr-DUPHOS
NORPHOS
DUANPHOS
9
31%
51%
1: 2
3: 1
4:1
>100:1
2:1
3:1
36:1
21:1
55:1
12:1
93:1
87:1
86:1
49:1
-
-
100%
100%
100%
100%
100%
100%
100%
100%
100%
100%
100%
100%h
-
-
26%
2%
20%
40%
34%
63%
82%
88%
89%
98%
10
BIBOP
BIBOP
BIBOP
MeO-BIBOP
Cu(OAc)2H2O
Cu(isobutyrate)2
Cu(isobutyrate)2
The proposed catalytic cycle is based on a Cu-alkoxide mediated
B/Cu exchange with the propargyl borolane 1 to generate an allenyl
Cu intermediate 3 (Scheme 1). After propargylation of an aldehyde,
a 1.5 equiv of 1. b Molar conversion. c Site selectivity between 7 and
8. d Absolute enantiomeric excess determined by chiralcel OJ-H HPLC.
e No LiOtBu. f 20 °C. g Reactions conducted at -30 °C with 7% Cu
salt, 9% ligand, and 7% LiOtBu. h 97% Isolated yield. See Supporting
Information for detailed optimization tables and ligand screen.
Scheme 1. Proposed Mechanism for a Cu Catalyzed
Propargylation of Aldehydes with a Propargyl Borolane
a Cu-alkoxide species would be regenerated, and a catalytic cycle
would be established. The two key operations in this catalytic cycle
have been separately demonstrated in an analogous B/Cu exchange
with an allyl borolane reagent9 and propargylation with an allenyl
copper species.3b Consistent with this model, a slow background
reaction between the parent aldehyde 6 and the borolane reagent 1
was observed with or without a catalytic copper halide catalyst.
Based on the previously shown B/Cu exchange with a Cu(I)
alkoxide complex,9b,10 the use of catalytic Cu(I)-tert-butoxide was
attempted which rapidly promoted the propargylation of p-anisal-
dehyde with moderate site selectivity for the alkynyl over the allenyl
product (Table 1). The use of phosphine ligands dramatically
improves the site selectivity for the homopropargylic alcohol, and
an enantioselective reaction was achieved by utilizing our recently
disclosed air stable BIBOP ligands.11 Variation of the copper
precatalyst moderately improved the enantioselectivity. A more
pronounced effect on the enantioselectivity was observed when the
methoxy derivative (MeO-BIBOP) of the parent BIBOP ligand was
employed.
After establishing highly enantioselective conditions, the scope of
the copper catalyzed asymmetric propargylation was examined (Table
2). High enantioselectivities (93-99% ee) and yields were achieved
for aromatic and alkenyl aldehydes. Only a slight decrease in
enantioselectivity (90% ee) was observed for the aliphatic aldehyde
(entry 10). The method demonstrated good tolerance toward numerous
functional groups. For example, esters, nitriles, an aryl fluoride, and a
carbamate showed no impact on the asymmetric propargylation.
Heterocycles and substrates bearing a Lewis basic functional group
that have the potential to coordinate to Lewis acidic metals were also
9
7600 J. AM. CHEM. SOC. 2010, 132, 7600–7601
10.1021/ja103312x  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Substrate Scope for the Asymmetric Propargylationa
Scheme 2. Application toward the Synthesis of Chiral
Dihydropyranone 16
In conclusion, the highly enantioselective copper catalyzed
propargylation of aldehydes with a propargyl borolane reagent
provides an operationally simple method for the preparation of
synthetically useful chiral homopropargylic alcohols.
Supporting Information Available: Complete optimization studies,
determination of absolute configuration, experimental procedures, char-
1
acterization data, and copies of chiral HPLC chromatograms, H and
13C NMR spectra for all products. This material is available free of
charge via the Internet at http://pubs.acs.org.
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a 1.5 equiv of 1. b Isolated yields. c Enantiomeric excess determined
by chiralcel OJ-H, OD-H, or chiralpak AD-H HPLC. d Reaction
performed at -30 to 0 °C for 48 h. See Supporting Information for
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