Highly enantioselective 1,4-conjugate addition of dialkylzinc to α,β-unsaturated lactone catalyzed by diphosphite-copper complexes

Article abstract of DOI:10.1016/S0040-4039(03)01788-X

The 1,4-addition of diethylzinc and dimethylzinc to 5,6-hydro-2H-pyran-2-one using new chiral diphosphite-copper catalysts gave products in up to 98% ee.

Full text of DOI:10.1016/S0040-4039(03)01788-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7217–7220
Highly enantioselective 1,4-conjugate addition of dialkylzinc to
a,b-unsaturated lactone catalyzed by diphosphite–copper
complexes
Liang Liang,a,b Liming Su,a Xingshu Lia and Albert S. C. Chana,*
aOpen Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Discovery and Synthesis† and
Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, PR China
bFaculty of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, PR China
Received 30 April 2003; revised 3 July 2003; accepted 14 July 2003
Abstract—The 1,4-addition of diethylzinc and dimethylzinc to 5,6-hydro-2H-pyran-2-one using new chiral diphosphite–copper
catalysts gave products in up to 98% ee.
© 2003 Elsevier Ltd. All rights reserved.
The enantioselective 1,4-conjugate addition to a,b-
unsaturated lactones is a reaction of high interest
because the chiral lactone products constitute impor-
tant subunits in many natural products such as
sesquiterpenes,1 a-methylene lactones2 and macrolides.3
In addition, many lactone compounds exhibit impor-
tant biological properties and function as semiochemi-
cals, flavours and fragrances, or as antibiotics or
cytostatics. Enders et al. reported the preparation of
b-stereogenic lactone derivatives via reagent-controlled
asymmetric Michael addition of
a stoichiometric
amount of chiral reagent to a non-chiral acceptor.4
The investigation of accessing chiral lactone com-
pounds by catalytic asymmetric synthetic method with
non-chiral starting material and catalytic amount of
Keywords: asymmetric catalysis; 1,4-conjugate addition; stereoselective synthesis; diphosphite ligands; a,b-unsaturated lactones.
* Corresponding author. E-mail: bcachan@polyu.edu.hk
† A University Grants Committee Areas of Excellent Scheme in Hong Kong.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01788-X

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L. Liang et al. / Tetrahedron Letters 44 (2003) 7217–7220
chiral source should be of high scientific and commer-
cial interest. The first attempt on that was reported in
1981 by Yoshikawa et al. who obtained lactones via
catalytic asymmetric hydrogenation of cyclic anhy-
drides with ee’s up to 20%.5 Thereafter, another route
was employed for chiral lactones with ee’s up to 94%
via DIOP-Rh catalyzed asymmetric hydrogenation of
itaconic acid esters, followed by selective hydride reduc-
tion.6 Doyle et al. developed a highly enantioselective
carbene insertion into an unactivated CꢀH bond of
diazoacetate with up to 96% ee by using a chiral
dirhodium(II) carboxamidate catalyst.7 Tomioka et al.
reported an enantioselective conjugate addition route in
which Grinard reagents reacted with 5,6-dihydro-2H-
pyran-2-one in the presence of 32 mol% of proline-
based chiral amidophosphines with up to 90% ee.8
Previously we also reported the enantioselective conju-
gate addition of diethylzinc to a,b-unsaturated lactones
with high enantioselectivities in the presence of copper
salts and chiral diphosphite ligands (2 mol%) derived
from binaphthol. When (S,S,S)-1 was used as chiral
ligand in the reaction, 8a was obtained in 73% ee.
Replacing the bridging part of (S,S,S)-1 from S-
binaphthol to achiral 3,3%,5%,5-tetra-tertbutyl-1,1%-bi-2-
phenol afforded (S,S)-2, which was utilized as chiral
ligand in the same reaction to give the chiral lactone in
up to 92% ee.9 Recently Reetz et al. reported the second
example in conjugate addition of ZnEt2 to lactones with
ee’s up to 88% by using ferrocene-based diphosphonites
and copper salts.10 In this paper, we report our recent
study on the copper-catalyzed enantioselective conju-
gate addition of dialkylzinc to 5,6-dihydro-2H-pyran-2-
one (Scheme 1).
Scheme 1.
phenomenon and our previous observation of the effec-
tiveness of (S,S,S)-1 and (S,S)-2, it was of interest to
modify (S,S,S)-1 by replacing some or all S-binaphthol
units to S-H8-binaphthol. (S,S,S)-3 was obtained by
replacing the bridging S-BINOL group to S-H8-
BINOL group.14 This modified ligand gave only 65% ee
in the conjugate addition (entry 1 of Table 1). Replac-
ing the terminal parts of (S,S,S)-3 from S-binaphthol
to S-H8-binaphthol gave (S,S,S)-4, which gave higher
ee value (81%) than those from using (S,S,S)-1 or
(S,S,S)-3 in the conjugate addition of diethylzinc to 7.
Further ligand modification led to the more effective
ligand (S,S,S)-5 and (S,R,S)-6 which gave up to 98% ee
in the reaction. The results of the catalytic reactions are
summarized in Tables 1 and 2. When the absolute
configuration of the bridging BINOL was different
from the terminal H8-BINOL, the catalyst exhibited
significantly higher enantioselectivity in the reaction
(entries 3 versus 6 and 4 verus 5 in Table 1). Interest-
ingly the same configuration of 8a was obtained
whether 4, 5 or 6 was used, indicating the dominant
effect of the terminal moieties in the chiral ligand. In
the investigation of the factors governing the rate and
enantioselectivity of the reaction by using 5 and 6, a
profound solvent effect was observed. In toluene, ethyl
acetate, dichloromethane and diethyl ether, the reaction
proceeded smoothly with good yield and high enan-
tioselectivity (Table 1, entries 7, 9, 10 and 12). The
effect of catalyst concentration on the enantioselectivity
was examined and it was found that lower catalyst
Previous studies by us11 and others12 showed that chiral
catalysts derived from partially hydrogenated binaph-
thyl species, 5,5%,6,6%,7,7%,8,8%-octahydro-1,1-bi-2-naph-
thyl exhibited higher activity and enantioselectivity
than those prepared from binaphthol in certain asym-
metric reactions due to the steric and electronic modu-
lation in the H8-binaphthyl backbone. Based on this
Table 1. Enantioselective 1,4-addition of diethylzinc to 5,6-dihydro-2H-pyran-2-one
Entrya
Ligand
[Cu] (10−3M)
Solvent
Yield (%)
eec (%) (+, R)d
1
2
3
(S,S,S)-3
(S,S,S)-4
(S,S,S)-5
(S,S,S)-5
(S,R,S)-6
(S,R,S)-6
(S,R,S)-6
(S,R,S)-6
(S,R,S)-6
(S,R,S)-6
(S,R,S)-6
(S,R,S)-6
(S,R,S)-6
4.00
4.00
4.00
4.00
4.00
4.00
1.67
1.25
1.67
1.67
1.67
1.67
1.67
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Toluene
EA
THF
CH2Cl2
1,4-Dioxane
81
78
76
77
70
79
81
82
97
82
13
64
44
65
81
90
91
97
96
97
98
94
95
61
93
83
4b
5b
6
7
8
9
10
11
12
13
a All reactions were carried out at −30°C for 18 h; substrate:copper:ligand:Zt2Zn=100:1:2:150–200 (molar ratio); CuOTf was used as copper
source unless otherwise indicated.
b Cu(OTf)2 was used as copper source.
c The ee values of 8a was determined by GC with a Chiraldex A-AT column (30 m×0.25 mm).
d The absolute configuration was assigned by comparing the optical rotation value with the result in Ref. 13.

L. Liang et al. / Tetrahedron Letters 44 (2003) 7217–7220
7219
Table 2. Enantioselective 1,4-addition of dimethylzinc to 5,6-dihydro-2H-pyran-2-one
Entrya
Ligand
[Cu] (10−3M)
Solvent (mL)
Time (h)
Yield (%)
eec,d (%)
1
2
(S,S,S)-3
(S,S,S)-4
(S,S,S)-5
(S,S,S)-5
(S,R,S)-6
(S,R,S)-6
(S,R,S)-6
(S,R,S)-6
(S,R,S)-6
(S,R,S)-6
5.00
5.00
5.00
5.00
5.00
5.00
1.66
5.00
5.00
5.00
Toulene
Toulene
Toulene
Toulene
Toulene
Toulene
Toulene
Et2O
28
28
28
28
28
28
34
34
34
34
57
51
66
48
56
39
49
25
10
60
43
54
69
69
82
75
85
68
63
72
3
4b
5
6b
7
8
9
10
EA
CH2Cl2
a All reactions were carried out at 0°C with CuOTf as copper source except otherwise indicated; substrate:copper:ligand=100:1:2 (molar rate).
b Cu(OTf)2 was used as copper source.
c The ee values of 8b was determined by GC with a Chiraldex A-AT column (50 m×0.25 mm).
d The absolute configurations of all the products were found to be R by comparimg the corresponding optical rotation values with that of Ref.
5.
concentration gave better product ee’s (Table 1, entries
6–8). The highest enantioselectivity obtained was 98%.
(b) Hoffmann, H. M. R.; Rabe, J. Angew. Chem. 1985,
97, 96–108; Angew. Chem., Int. Ed. Engl. 1985, 24, 94–
110; (c) Sarma, J. C.; Sharma, R. P. Heterocycles 1986,
441–457; (d) Ito, M. Pure Appl. Chem. 1991, 63, 13–22.
3. For reviews, see: (a) Nicolaou, K. C. Tetrahedron 1977,
33, 683–710; (b) Masamune, S.; Bates, G. S.; Corcoran, J.
W. Angew. Chem., Int. Ed. Engl. 1977, 16, 587–588; (c)
Rossa, L.; Vo¨gtle, F. Top. Curr. Chem. 1983, 113, 1–83;
(d) Paterson, I.; Mansuri, M. M. Tetrahedron 1985, 41,
3569–3624; (e) Boeckmann, R. K., Jr.; Goldstein, S. W.
In The Total Synthesis of Natural Products; Simon, J. A.,
Ed.; Wiley: New York, 1988; Vol. 7; p. 1.
4. (a) Enders, D.; Gro¨bner, R.; Runsink, J. Synthesis 1995,
947–951; (b) Enders, D.; Teschner, P.; Gro¨bner, R.;
Raabe, G. Synthesis 1999, 237–242; (c) Enders, D.; Sun,
H.; Leusink, F. R. Tetrahedron 1999, 55, 6129–6138.
5. Osakada, K.; Obana, M.; Ikariya, T.; Saburi, M.;
Yoshikawa, S. Tetrahedron Lett. 1981, 22, 4297–4300.
6. (a) Tanaka, M.; Mukaiyama, C.; Mitsuhashi, H.;
Maruno, M.; Wakamatsu, T. J. Org. Chem. 1995, 60,
4339–4352; (b) Landais, Y.; Robin, J. P.; Lebrun, A.
Tetrahedron 1991, 47, 3787–3804; (c) Kosugi, H.; Tagami,
K.; Takahashi, A.; Kanna, H.; Uda, H. J. Chem. Soc.,
Perkin Trans. 1 1989, 935–943.
The effect of copper source for the catalyst was rela-
tively insignificant (Table 1, entries 3 versus 4 and 5
versus 6).
The 1,4-conjugate addition of dimethylzinc to 5,6-dihy-
dro-2H-pyran-2-one (7) was also investigated. Table 2
summarized the results obtained under various reaction
conditions. Ligand 6 always exhibited better enantiose-
lectivity than those obtained by using ligands 3, 4 or 5
under otherwise identical conditions. The enantioselec-
tivity of the reaction was found to be strongly affected
by the solvent used. Among the four different solvents
(toluene, diethyl ether, ethyl acetate and dichloro-
methane) used, toluene gave the best product ee.
In summary, new chiral diphosphite ligands derived
from H8-binaphthol were found to be effective in the
enantioselective copper-catalyzed 1,4-addition of
diethylzinc and dimethylzinc to 5,6-dihydro-2H-pyran-
2-one, giving rise to enantiomeric excesses of up to 98%
and 85%, respectively. To the best of our knowledge,
these are the best ee values achieved for these reactions
to date.
7. (a) Bode, J. W.; Doyle, M. P.; Protopopova, M. N.;
Zhou, Q.-L. J. Org. Chem. 1996, 61, 9146–9155; (b)
Doyle, M. P.; Protopopova, M. N.; Zhou, Q.-L.; Bode, J.
W.; Simonsen, S. H.; Lynch, V. J. Org. Chem. 1995, 60,
6654–6655.
Acknowledgements
8. Kanai, M.; Tomioka, K. Tetrahedron Lett. 1995, 36,
4275–4278.
9. Yan, M.; Zhou, Z. Y.; Chan, A. S. C. Chem. Commun.
2000, 115–116.
We thank the University Grants Committee Areas of
Excellence Scheme in Hong Kong (AoE P/01-10), The
Hong Kong Polytechnic University ASD Fund and The
Hong Kong Research Grants Council (Project number
PolyU5152/98P) for financial support of this study.
10. Reetz, M.; Gosberg, T. A.; Moulin, D. Tetrahedron Lett.
2002, 43, 1189–1191.
11. (a) Zhang, F.-Y.; Kwok, W. H.; Chan, A. S. C. Tetra-
hedron: Asymmetry 2001, 12, 2337–2342; (b) Zhang, F.-
Y.; Chan, A. S. C. Tetrahedron: Asymmetry 1997, 8,
3651–3655; (c) Chan, A. S. C.; Zhang, F.-Y.; Yip, C.-W.
J. Am. Chem. Soc. 1997, 119, 4080–4081; (d) Zhang,
F.-Y.; Pai, C.-C.; Chan, A. S. C. J. Am. Chem. Soc. 1998,
120, 5808–5809; (e) Zhang, F.-Y.; Chan, A. S. C. Tetra-
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References
1. Yoshioka, H.; Mabry, T. J.; Timmermann, B. N.
Sesquiterpene Lactones; University of Tokyo Press:
Tokyo, 1973.
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12. (a) Zhang, X.; Taketomi, T.; Yoshizumi, T.;
Kumobayashi, H.; Akutagawa, S.; Mashima, K.; Takaya,
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Kumobayashi, H.; Ohta, T.; Nozaki, K.; Takaya, H. J.
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1947–1950.
and 1.5 equiv. of neat Et2Zn were added sequentially.
The reaction was quenched by the addition of 1.5–2 mL
of a saturated solution of NH4Cl. The product was
extracted with Et2O (three times, 2.0 mL each), dried
with MgSO4, followed by the removal of volatiles in
vacuo. The yield and ee value of the product were
determined by GC with a chiral capillary column using
dodecane as an internal standard. Ligands 3–6 were
synthesized according to our previously reported method9
by using H8-BINOL to replace the appropriate BINOL
units. [[(S)-1,1%-bi-2-naphthol]bi[(S)-2,2%-dihydroxy-5,5%,6,
6%,7,7%,8,8%-octahydro-1,1%-binaphthyl]bisphosphite] (5): 1H
NMR (CD2Cl2): l 8.08 (d, J=8.5 Hz, 2H), 7.98 (d,
J=8.5 Hz, 2H), 7.56 (d, J=9.0 Hz, 2H), 7.44 (t, J=7.0
Hz, 2H), 7.32–7.20 (m, 6H), 7.01 (d, J=8.5 Hz, 2H), 6.84
(d, J=8.0 Hz, 2H), 6.03 (d, J=7.5 Hz, 2H), 2.82–2.60
(m, 8H), 2.57–2.53 (m, 4H), 2.16–2.07 (m, 4H), 1.80–1.66
(m, 12H), 1.49–1.42 (m, 4H); 13C NMR (CD2Cl2) l
145.9, 145.5, 138.5, 137.6, 135.1, 134.2, 134.1, 131.0,
130.1, 129.3, 129.1, 128.3, 128.2, 127.6, 127.0, 125.9,
125.2, 122.6, 120.0, 118.9, 118.7, 29.1, 27.7, 22.7, 22.5
ppm; 31P NMR (CD2Cl2) l 138.39 ppm; [h]2D0=+98.0
(c=1.0, toluene); HRMS calcd for C60H52O6P2: 930.3239,
found: 930.3161. [[(R)-1,1%-bi-2-naphthol]bi[(S)-2,2%-dihy-
droxy-5,5%,6,6%,7,7%,8,8%-octahydro-1,1%-binaphthyl]bisphos-
phite] (6): mp 167°C; 1H NMR (CD2Cl2): l 8.05 (d,
J=9.0 Hz, 2H), 8.00 (d, J=8.0 Hz, 2H), 7.49–7.47 (m,
4H), 7.29 (td, J=7.3, 1.5 Hz, 2H), 7.20–7.18 (m, 2H),
6.95 (d, J=8.0 Hz, 2H), 6.73 (d, J=7.0 Hz, 2H), 6.42 (d,
J=8.0 Hz, 2H), 5.3 (d, J=8.5 Hz, 2H), 2.71–2.47 (m,
12H), 2.09–2.04 (m, 4H), 1.69–1.61 (m, 12H), 1.45–1.41
(m, 4H); 13C NMR (CD2Cl2): l 148.4, 145.8, 138.54,
138.1, 137.1, 135.2, 134.2, 134.0, 131.2, 130.3, 129.3,
129.1, 128.8, 128.2, 127.5, 127.1, 126.1, 125.3, 123.1,
121.4, 118.8, 118.5, 29.1, 29.1, 27.8, 27.7, 22.7, 22.7, 22.5,
22.5 ppm; [h]2D0=+87.9 (c=1.0, toluene); HRMS calcd
for C60H52P2O6: 930.3239, found: 930.3306.
14. Experimental section: Unless otherwise indicated, all
experiments were carried out under dry N2 atmosphere.
Toluene, diethyl ether, THF and 1,4-dioxane were dried
over sodium and distilled immediately before use.
Dichloromethane was distilled over CaH2. PCl3 was dis-
tilled and BINOL was dried by toluene azeotrope method
before use. Commercially available 5,6-dihydro-2H-
pyran-2-one (98%, ACROS), Cu(OTf)2 (98%, ACROS),
ZnEt2 (Pure, Aldrich) were used without further purifica-
1
tion. 31P, H and 13C NMR spectra were recorded on a
Varian AS500 spectrometer. Enantiomer excess values
were determined by chiral GC analysis (Chiraldex A-TA
column 50 m×0.25 mm). High-resolution mass spec-
trometry was performed using a Finnigan MAT 95S
model spectrometer. Optical rotations were measured on
a Perkin-Elmer 241 MC (at 20°C). GC analyses were
performed on an HP 5890 apparatus equipped with FID.
Typical experimental procedure for the Cu-catalyzed con-
jugate addition of organozinc reagents to 5,6-hydro-2H-
pyran-2-one: The reaction was carried out under nitrogen
atmosphere using dried glassware. The catalyst was pre-
pared in situ by stirring 1 mol% of (CuOTf)2·C6H6 (or Cu
(OTf)2) and 2 mol% of ligand in 2–8 mL of dry Et2O for
20–30 min and then at −30 to 0°C substrate (1.0 equiv.)