Copper-catalyzed conjugate addition on macrocyclic, cyclic, and acyclic enones with a chiral phosphoramidite ligand having a C2-symmetric amine moiety

Article abstract of DOI:10.1016/S0957-4166(02)00206-9

A binaphthol-based phosphoramidite ligand (4.2 mol%) having a C₂-symmetric chiral amine moiety was examined for enantioselective 1,4-additions of dialkylzinc reagents to various macrocyclic, cyclic, and acyclic enones catalyzed by copper triflate·toluene complex (2 mol%) to afford high enantiomeric excess (up to >95% ee).

Full text of DOI:10.1016/S0957-4166(02)00206-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 801–804
Copper-catalyzed conjugate addition on macrocyclic, cyclic, and
acyclic enones with a chiral phosphoramidite ligand having a
C2-symmetric amine moiety
Yong Hyun Choi, Jun Young Choi, Hye Yon Yang and Yong Hae Kim*
Department of Chemistry, Center for Molecular Design and Synthesis, Korea Advanced Institute of Science and Technology,
Taejon 305-701, South Korea
Received 18 March 2002; accepted 26 April 2002
Abstract—A binaphthol-based phosphoramidite ligand (4.2 mol%) having a C2-symmetric chiral amine moiety was examined for
enantioselective 1,4-additions of dialkylzinc reagents to various macrocyclic, cyclic, and acyclic enones catalyzed by copper
triflate·toluene complex (2 mol%) to afford high enantiomeric excess (up to >95% ee). © 2002 Elsevier Science Ltd. All rights
reserved.
The asymmetric conjugate addition of organometallic
reagents to enones is an attractive synthetic method for
carbonꢀcarbon bond formation.1 A number of chiral
auxiliaries and stoichiometric reagents have been devel-
oped which allow asymmetric 1,4-addition reactions to
proceed in an enantioselective manner.1d Great efforts
have also been made to develop catalysts for asymmetric
conjugate additions of organozinc reagents to enones
using phosphorus–amidites,2 phosphite–oxazolines,3
amido–phosphine,4 diphosphite,5 sulfonamide,6 and
Schiff base7 ligands. Among them, copper and binaph-
thol–phosphorus type ligand complexes2,3,5 have been
developed for effective enantioselective 1,4-addition
reactions. Recently, highly enantioselective alkylation to
enones was reported by Feringa and co-workers using
chiral phosphorus–amidite ligands with a chiral sec-
ondary amine catalyst.2a,b While high enantiomeric
excesses were achieved for cyclohexenone, the enan-
tioselective 1,4-addition reaction to macrocyclic enones
resulted in unsatisfactory enantioselectivity. During the
study on asymmetric alkylations of macrocyclic enones,
we have established that a new binaphthol phospho-
ramidite ligand containing a chiral C2-symmetric pyrro-
lidine moiety is an excellent ligand for chiral copper
complexes which furnish high enantioselectivities in the
conjugate addition of dialkylzinc reagent to macrocyclic
enones. The chiral ligand (R,R,R)-1 has been applied to
the synthesis of (R)-(−)-muscone, a biologically intrigu-
ing natural product which has been synthesized by
various methods.8
Enantiomerically pure ligand 1 was easily prepared by
the reaction of (R)-binaphthol and (R,R)-chloroamidite
2 in the presence of triethylamine. (R,R)-Chloroamidite
2
was synthesized by the reaction of (R,R)-
diphenylpyrrolidine 3 with n-BuLi in tetrahydrofuran at
−15°C and then following addition of an excess of neat
PCl3 to THF solution of lithium amide (Scheme 1).10
Ph
N
Ph
HN
Ph
N
Ph
N
(R)-binaphthol, Et3N
PCl3, n-BuLi
O
O
O
O
Cl2P
P
P
toluene, rt, 5 h
THF, -15 oC
Ph
(R,R)-2
Ph
Ph
Ph
(R,R)-3
(S,R,R)-1
(R,R,R)-1
Scheme 1.
* Corresponding author. Tel.: +82-42-869-2818; fax: +82-42-869-5818; e-mail: yhkim@kaist.ac.kr
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00206-9

802
Y. H. Choi et al. / Tetrahedron: Asymmetry 13 (2002) 801–804
Table 1. The effect of reaction temperature and ligand configuration on the conjugate addition of diethylzinc to 2-cyclopenta-
decen-1-one 7b
O
O
Cu salt (2 mol%)
ligand-1 (4.2 mol%)
+ R2Zn
R
toluene, 5 h
(CH2)6
(CH2)6
4a n=3
4b n=6
5a n=3, R=Et
5b n=6, R=Et
5c n=6, R=Me
Entry
Ligand
Cu salt
Substrate
4b
4b
4b
4b
4b
4a
4b
R
Product
T (°C)
Yield (%)a
Ee (%)b,d
1c
2c
3
4
5
(R,R,R)-1
(S,R,R)-1
(R,R,R)-1
(R,R,R)-1
(R,R,R)-1
(R,R,R)-1
(R,R,R)-1
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
(CuOTf)2·toluene
(CuOTf)2·toluene
(CuOTf)2·toluene
Me
Me
Me
Me
Me
Et
5c
5c
5c
5c
5c
5a
5b
−20
−20
−40
−78
−40
−40
−40
90
75
85
–
87
90
95
86 (R)
55 (S)
93 (R)
–
95 (R)
71 (R)
74 (R)
6
7
Et
a Isolated yield.
b The ee was determined by chiral HPLC on a chiraldex AS column.
c The reaction time was 3 h.
d The absolute configuration was determined from the specific rotation (Ref. 13).
(95%, 74% ee) (entry 7 in Table 1). The Alexakis group
reported the synthesis of (R)-(−)-muscone using a cata-
lytic amount of copper (2 mol%) and chiral phosphite
ligand (4 mol%) with somewhat low yield (53%) and
moderate enantioselection (79% ee).12 However, we
were able to obtain (R)-(−)-muscone in high yield
through the highly enantioselective 1,4-addition of
dimethylzinc to 4a (95% ee) by utilizing (R,R,R)-1 as a
catalytic ligand.11
The chiral amine (R,R)-3 was prepared by the known
method.9
In order to establish optimal conditions for the addi-
tion reaction, 2-cyclopentadecen-1-one 4b was chosen
as a typical substrate and tested with chiral ligand 1.
The results obtained are summarized in Table 1. In
most cases, complete conversions occurred and the
1,2-adduct was not detected by gas chromatographic
analysis. The highest enantioselectivity was obtained at
−40°C in toluene (95% ee, entry 5). The 1,4-adduct
could not be obtained at −78°C: starting material 4a
was recovered (entry 4). The enantioselectivity
decreased considerably as the reaction temperature was
elevated to −15 or 0°C. Use of (CuOTf)2·toluene com-
plex gave somewhat higher enantioselectivity than the
Cu(OTf)2 system (entries 3 and 5). Ligand configura-
tion appears to be important because the mismatched
ligand (S,R,R)-1 diminished both the rate, conversion
(75%) and enantioselectivity (55% ee) of the reaction
(entry 2).
As illustrated in Table 2, small (five-, six-, and seven-
membered) rings were examined with 4.2 mol% of
(R,R,R)-1 and 2 mol% of (CuOTf)2·toluene complex.
The conversions were determined by GC analysis. In all
cases, reactions were completed within 3 h and the
regioselectivity for the 1,4-adducts over the 1,2-adducts
was higher than 99% (yield: 98%, entry 1 in Table 2).
The five-, six- and seven-membered enones gave the
corresponding 1,4-products with ee of 52–93%. In the
case of 2-cyclopenten-1-one 6b, the conversion was
almost quantitative to the corresponding 1,4-adduct 7b
by GC analysis, but the isolated yield was somewhat
lower probably due to the volatility of 7b (entry 2 in
Table 2).
The conformation of the macrocyclic enones could be
s-trans or s-cis (Fig. 1). Since the reactions of 4b
mediated by the (R,R,R)-1 complex to give products 5
resulted in the same diastereofacial outcome, it was
thought that the 1,4-addition reaction might occur from
the 4b-s-cis form as in acyclic enone 8 (Scheme 2).
Thus, 12- and 15-membered enones were tested using
(R,R,R)-1 and (CuOTf)2·toluene complex. In the 1,4-
addition of diethylzinc to 4a, the ligand (R,R,R)-1
complex gave 5a (90%) with high enantioselectivity
(71% ee, entry 6, Table 1). Enone 4b was reacted with
diethylzinc with (R,R,R)-1 at −40°C for 3 h to give 5b
O
O
4a-s-cis
4a-s-trans
Figure 1.

Y. H. Choi et al. / Tetrahedron: Asymmetry 13 (2002) 801–804
803
.
(CuOTf)2 toluene (2 mol%)
O
O
R,R,R- 1 (4,2mol%)
toluene, -20 oC, 3 h
+ Et2Zn
Ph
Ph
Ph
Ph
9
8
88%, 68% ee (S)
Scheme 2.
Table 2. Copper-catalyzed conjugate addition to cyclic
enones 6a–c
References
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.
O
O
(CuOTf)2 toluene (2 mol%)
R,R,R- 1 (4,2mol%)
toluene, -40 oC, 3 h
+ Et2Zn
( )n
( )n
6a n=1
6b n=0
6c n=2
7a n=1
7b n=0
7c n=2
Entry
Substrate
Product
Yield (%)a
Ee (%)b,d
1
2
3
6a
6b
6c
7a
7b
7c
98
78
97
93 (R)c
52 (R)c
76 (R)c
a Isolated yield.
b The ee was determined by chiral GC on a Chiraldex G-DM
(30×0.25 mm) capillary column.
c The absolute configuration was determined by chiral GC on a
chiraldex G-DM column compared with the known reference (Ref.
3).
d The absolute configuration was not determined.
3. Kno¨bel, A. K. H.; Escher, I. J.; Pfaltz, A. Synlett 1997,
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4. Hu, X.; Chen, H.; Zhang, X. Angew. Chem., Int. Ed.
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The acyclic a,b-unsaturated ketone, trans-chalcone 8
reacted with diethylzinc in the presence of (R,R,R)-1
(4.2 mol%) and (CuOTf)2·toluene complex (2 mol%) at
−20°C in toluene to afford 9 in high yield and moderate
enantioselectivity (Scheme 2). When the reaction tem-
perature was decreased to −40°C, the reaction did not
proceed at all. The absolute configuration of the
product is known.3
5. (a) Alexakis, A.; Vastra, J.; Burton, J.; Benjamine, C.;
Mangeney, P. Tetrahedron Lett. 1998, 39, 7869–7872; (b)
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Chem. Eur. J. 2001, 7, 2628–2634.
In conclusion, the binaphthol-based phosphorusamidite
ligand bearing a C2-symmetric pyrrolidine could be
successfully utilized as a chiral ligand in the copper-cat-
alyzed enantioselective conjugate addition. In particu-
lar, the enantioselective 1,4-addition reaction using
catalytic amount of chiral ligand (R,R,R)-1 was applied
to synthesis of chiral macrocyclic ketones such as (R)-
(−)-muscone with high eanantioselectivity. Until now
there is only one reported example of asymmetric 1,4-
additions to macrocyclic enones using a catalytic chiral
ligand.10
7. Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am.
Chem. Soc. 2001, 123, 755–756.
8. (a) Nelson, K.; Mash, E. A. J. Org. Chem. 1986, 51,
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Acknowledgements
This work was supported by Grant No. R03-2001-
00033 from the Korea Science
Foundation.
&
Engineering

804
Y. H. Choi et al. / Tetrahedron: Asymmetry 13 (2002) 801–804
Commun. 1991, 101–102; (g) Oppelzer, W.; Radinov, N.
pure chiral ligand (R,R,R)-1 as a white solid in 55% yield
(99.8% ee); [h]D24 −556.2 (c 1.0, CHCl3); 1H NMR
(CDCl3) l (ppm) 7.12–7.94 (m, 22 H), 5.11–5.04 (m, 2
H), 2.41–2.34 (m, 2 H), 1.76–1.68 (m, 2 H); 13C NMR
(CDCl3), l (ppm) 144.55, 144.49, 132.88, 131.14, 130.59,
129.87, 128.11, 127.08, 126.82, 126.01, 125.81, 124.51,
121.90, 121.40, 63.37, 63.21, 34.19; HRMS observed
mass=537.1906 (calculated mass=537.1858).
J. Am. Chem. Soc. 1993, 115, 1593–1594; (h) Kamat, V.
P.; Hagiwara, H.; Suzuki, T.; Ando, M. J. Chem. Soc.,
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Taylor, N. J. Tetrahedron: Asymmetry 1995, 6, 409–418.
10. Synthesis of O,O%-(R)-(1,1%-dinaphthyl-2,2%-diyl)-4-((R,R)-
2,5-diphenylpyrrolidine)-(R)-dinaphthodioxaphosphephine
(R,R,R)-1
11. General procedure for the catalytic conjugate addition of
dialkylzinc to enones
A solution of (R,R)-trans-2,5-diphenylpyrrolidine 3 in
THF at −78°C under argon was treated dropwise with
n-butyllithium (2.5 M hexane). The reaction mixture was
then stirred for 1 h. Excess PCl3 (10 equiv.) was then
rapidly added to the lithium reagent. The reaction mix-
ture was allowed to warm to room temperature and
stirred for 2 h. The mixture was concentrated and
extracted with toluene. Evaporation of the solvent from
the combined extracts afforded the product as a pale-yel-
low oil (R,R)-2 which was used without further purifica-
tion.
A solution of (R)-binaphthol and triethylamine (5 equiv.)
in toluene was added dropwise to a solution of (R,R)-2 in
toluene at 0°C. After stirring for 12 h, the precipitated
Et3N·HCl was removed by filtration, and concentrated to
give the crude product which was purified by silica gel
column chromatography (EtOAc/hexane, 1/9) to give
A solution of (CuOTf)2·toluene complex (3.6 mg, 0.01
mmol) and chiral ligand (R,R,R)-1 (0.021 mmol) in tolu-
ene (3 mL) was stirred for 1 h. The colorless solution was
cooled to −40°C and enone (0.5 mmol) was added fol-
lowed by addition of a solution of dialkylzinc in toluene
(1.5 equiv.). After stirring for 3–5 h, the reaction mixture
was quenched with 1N aqueous HCl and extracted with
diethyl ether. The combined organic layers were washed
with brine, dried over MgSO4, filtered, and concentrated.
The crude product was purified by silica gel column
chromatography (EtOAc/hexane, 1/9) to give the 1,4-
addition products.
12. Alexakis, A.; Benha¨ım, C.; Fournioux, X.; van den
Heuvel, A.; Leveˆque, J.-M.; March, S.; Rosset, S. Synlett
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13. Branca, Q.; Fischli, A. Helv. Chim. Acta 1977, 925–944.