Dual stereoselection in the addition of diethylzinc to benzaldehyde by using highly structurally close ligands

Article abstract of DOI:10.1002/chir.21994

The screening of the catalytic activity in the diethylzinc reaction of a series of easily accessible (1S)-ketopinic-acid derived hydroxyamides, designed by key structure modifications of a parent highly active related bis(hydroxyamide), has allowed to fin

Full text of DOI:10.1002/chir.21994

CHIRALITY 24:255–261 (2012)
Dual Stereoselection in the Addition of Diethylzinc to Benzaldehyde
by Using Highly Structurally Close Ligands
´
´
´
ESTHER M. MARQUEZ SANCHEZ-CARNERERO, TOMAS DE LAS CASAS ENGEL,
*
BEATRIZ LORA MAROTO, AND SANTIAGO DE LA MOYA CERERO
Departamento de Quı´mica Orga´nica I, Universidad Complutense de Madrid, Facultad de Ciencias Quı´micas,
Ciudad Universitaria s/n, 28040-Madrid, Spain
ABSTRACT
The screening of the catalytic activity in the diethylzinc reaction of a series of
easily accessible (1S)-ketopinic-acid derived hydroxyamides, designed by key structure modifi-
cations of a parent highly active related bis(hydroxyamide), has allowed to find the first case of
dual stereoselection in highly structurally close ligands of such interesting chemically sustain-
able typology. The found striking dual stereoselection is explained on the basis of empiric
models for the acting zinc catalysts and involved controlling transition states, which are
supported by additional specific experimental structure-activity tests. Chirality 24:255–261,
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2012.
2012 Wiley Periodicals, Inc.
KEY WORDS: asymmetric catalysis; diethylzinc reaction; dual stereoselection; ketopinic acid;
hydroxyamides
INTRODUCTION
one enantiomer is easily accessible from nature, which
makes the other enantiomer more expensive or even com-
One of the most useful asymmetric reactions is the cata-
lyzed enantioselective addition of organozinc reagents to
aldehydes, which allows the straightforward preparation of
valuable enantioenriched secondary-alcohol building blocks
(Scheme 1).1–11 Once the main grounds of its mechanism
have been established (on the basis of the formation of a chi-
ral metal-chelate catalyst)1 and different series of active
ligands, mainly b-(dialkylamino)alcohols such as Nuggent’s
MIB 1 (Fig. 1),12 have been developed, the current research
in this important reaction is focused in finding versatile
ligands able to promote the highly enantioselective addition
of a wide range of organozinc reagents to a wide range of
aldehydes (e.g., Wang’s ligand 2 in Fig. 1),13 as well as
designing sustainable reactions according to the principles
and practices of the Green Chemistry.14
The main basis to achieve sustainable additions of orga-
nozinc reagents to aldehydes are related to the develop-
ment of ligands which can promote the reaction without
participation of other metals (e.g., titanium), are obtained
straightforwardly from accessible starting materials (cheap
ligands) and, if possible, can be reused several times. In
this sense, we have recently demonstrated that certain iso-
borneol-based ketopinic-acid derived hydroxyamides [e.g.,
bis(hydroxyamide) 3 in Fig. 1] constitute a new class of
ligands able to efficiently promote the enantioselective
addition of organozinc reagents to aldehydes in absence of
titaninum.15 Moreover, these ligands are easily obtained
from an enantiomerically pure renewable starting material
coming from the Chiral Pool (available camphor-derived
ketopinic acid), as well as inert enough to develop long-life
reusable catalysts.15
mercially unavailable.16
This important problem has been addressed in limited
cases by switching the sense of the stereoselection exerted
by the acting chiral catalyst (dual stereoselection, dual
switch, or stereoselection switch), which is mainly achieved
by modifying the structure of the parent chiral ligand. In this
line, most of the effective stereoselection switches reported
up to date for the enantioselective addition of organozinc
reagents to aldehydes have been achieved by designing
pseudo-enantiomeric (e.g., 4 vs. 5 in Fig. 2)16 or epimeric
ligands (e.g., 6 vs. 7 in Fig. 2),17 as well as by introducing
bulky groups in specific places of the parent structure (e.g.,
8 vs. 9 in Fig. 2).18 Unfortunately, in most of these cases,
the important structural modifications introduced in the
switching ligand make its preparation more complicated and,
therefore more expensive. This problem could be solved by
designing highly structurally close dual ligands, therefore
with minimal differences in their synthesis.
According to all the above exposed, we became interested
in checking a possible dual stereoselection in highly struc-
turally close (1S)-ketopinic-acid derived hydroxyamide-based
ligands, which would enhance the potential of these com-
pounds as a new class of sustainable ligands for the enantio-
selective addition of organozinc reagents to aldehydes.
EXPERIMENTAL
Common solvents were dried and distilled by standard procedures. All
starting materials and reagents were obtained commercially and used
without further purifications. Flash chromatography purifications were
performed on silica gel (230–400 mesh ASTM). Melting points are
uncorrected. NMR spectra were recorded at 208C in CDCl3 and the
The development of a useful chiral ligand requires the
accessibility to both enantiomers of such ligand, to have
access to both enantiomers of the reaction product. Unfortu-
nately, the two enantiomers of the mentioned chiral hydrox-
yamides are not equally accessible, since both enantiomers
of the starting ketopinic acid are not commercially available.
This is a general situation for most of the chiral agents
derived from chiral natural products, where normally only
*Correspondence to: Santiago de la Moya Cerero, Departamento de Quı´mica
Orga´nica I, Universidad Complutense de Madrid, Facultad de Ciencias Qu´ı-
micas, Ciudad Universitaria s/n, 28040-Madrid, Spain.
E-mail: santmoya@quim.ucm.es
Received for publication 15 April 2011; Accepted 2 November 2011
DOI: 10.1002/chir.21994
Published online 25 January 2012 in Wiley Online Library
(wileyonlinelibrary.com).
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VV
2012 Wiley Periodicals, Inc.

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SANCHEZ-CARNERERO ET AL.
256
Scheme 1. Enantioselective addition of organozinc reagents to aldehydes.
residual solvent peak was used as internal standard. FTIR spectra were
obtained using the thin-layer technique. GC analyses were realized at
1208C in a chromatograph equipped with a capillary silicon-gum (SGL-1)
column and a FID, and using nitrogen as mobile phase. Chiral-HPLC
analyses were realized at r.t. in a chromatograph equipped with a Chiral-
pak-IC column and a DAD, and using hexane/isopropanol (98:2) as
mobile phase. MS were recorded using the ESI ionization technique. FT
was used for the HRMS determinations.
Fig. 2. Some examples of effective dual stereoselection in the enantiose-
lective addition of diethylzinc to benzaldehyde.
(0.08 g, 2.0 mmol). The mixture was refluxed for 24 h under argon. After
cooling it down to room temperature, water (0.01 ml) was added and the
resulting mixture was concentrated under reduced pressure to evaporate
methanol. The obtained residue was diluted with chloroform (10 ml).
Water (10 ml) was added and the resulting layers separated. The aque-
ous layer was extracted with chloroform (3 3 5 ml). The combined or-
ganic layers were washed with brine (1 3 10 ml) and dried with anhy-
drous Na2SO4. After filtration and solvent evaporation under reduced
pressure, the residue was purified by flash column chromatography
(silica gel, hexane/ethyl acetate 1:1; 0.14 g, 95% yield). White solid. Mp:
213–2148C. [a]D20 215.8 (c 0.26, CHCl3). 1H NMR (CDCl3, 300 MHz), d:
4,18 (dd, J 5 7.6 Hz, J 5 4.2 Hz, 1H), 3.74–3.42 (m, 8H), 2.12 (s, 3H),
2.05–1.78 (m, 5H), 1.66 (dd, J 5 4.2 Hz, J 5 4.2 Hz, 1H), 1.55–1.47 (m,
1H), 1.39 (s, 3H), 1.29–1.11 (m, 1H), 1.15 (s, 3H) ppm. 13C NMR
(CDCl3, 75 MHz), d: 172.0 (NꢀꢀC¼O), 169.2 (NꢀꢀC¼O), 78.0
(CHꢀꢀOH), 60.6 (C), 50.6 (C), 46.2 (CH2), 44.8 (CH), 44.4 (CH2), 43.7
(CH2), 41.8 (CH2), 41.5 (CH2), 30.0 (CH2), 27.0 (CH2), 22.1 (CH3), 21.6
(CH3), 21.3 (CH3) ppm. FTIR, m: 3322 (br, w), 1614 (str) cm21. MS
(ESI), m/z (%): 318 ([M11123]1, 24), 317 ([M123]1, 100), 295
([M11]1, 3). HRMS (ESI), m/z: 317.1841 (calcd for C16H26N2NaO3:
317.1836).
Ligand Syntheses
Ligand 10:
(1S,4R)-1-[(4-Acetylpiperazin-1-yl)carbonyl]-7,7-dimethyl-
norbornan-2-one [18(acetyl)]. In a round-bottom flask, equipped
with a magnetic stirrer, (1S)-ketopinic acid (16) (0.30 g, 1.6 mmol),
EDC hydrochloride (0.35 g, 1.8 mmol), DMAP (0.23 g, 1.8 mmol) and 1-
acetylpiperazine [17(acetyl)] (0.23 g, 1.8 mmol) were dissolved in
CH2Cl2 (6 ml) and the mixture was stirred at room temperature for 24 h.
Water (6 ml) was then added and the resulting layers were separated.
The aqueous layer was extracted with CH2Cl2 (3 3 3 ml). The combined
organic layers were washed successively with 10% HCl (1 3 5 ml), water
(1 3 5 ml), 10% NaOH (2 3 5 ml), water (1 3 5 ml), and brine (1 3 5
ml), and dried with anhydrous Na2SO4. After filtration and solvent evapo-
ration under reduced pressure, the residue was purified by flash column
chromatography (silica gel, hexane/ethyl acetate 2:1; 0.43 g, 93% yield).
White solid. Mp: 115–1178C. [a]D 213.9 (c 0.85, CHCl3). 1H NMR
20
(CDCl3, 300 MHz), d: 3.53–3.24 (m, 8H), 2.57 (ddd, J 5 18.5 Hz, J 5 4.8
Hz, J 5 2.8 Hz, 1H), 2.32–2.21 (m, 1H), 2.16–1.97 (m, 3H), 2.11 (s, 3H),
1.92 (d, J 5 18.5 Hz, 1H), 1.50–1.41 (m, 1H), 1.21 (s, 3H), 1.20 (s, 3H)
ppm. 13C NMR (CDCl3, 75 MHz), d: 212.5 (C¼O), 169.0 (NꢀꢀC¼O),
167.9 (NꢀꢀC¼O), 67.4 (C), 50.6 (C), 46.4 (CH2), 43.7 (CH2), 43.1 (CH),
41.6 (CH2), 27.3 (CH2), 27.0 (CH2), 21.3 (CH3), 21.2 (CH3), and 20.9
(CH3) ppm. FTIR, m: 1736 (str), 1634 (str) cm21. MS (ESI), m/z (%): 316
([M11123]1, 24), 315 ([M123]1, 100), 293 ([M11]1, 4). HRMS (ESI),
m/z: 315.1687 (calcd for C16H24N2NaO3: 315.1679).
Ligand 11:
(1S,4R)-1-{[4-(terc-Butoxycarbonyl)piperazin-1-yl]carbonyl}-
7,7-dimethylnorbornan-2-one [18(BOC)]. 1-(terc-Butoxycarbo-
nyl)piperazine [17(BOC)] (0.34 g, 1.8 mmol) was reacted following the
experimental procedure for the preparation of 18(acetyl). 0.55 g (98%
yield). White solid. Mp. 148–1508C. [a]D 212.1 (c 0.87, CHCl3). 1H
20
NMR (CDCl3, 300 MHz), d: 3.58–3.23 (m, 8H), 2.49 (ddd, J 5 18.5 Hz, J
5 5.1 Hz, J 5 2.7 Hz, 1H), 2.30–2.20 (m, 1H), 2.12–1.95 (m, 3H), 1.90 (d,
J 5 18.5 Hz, 1H), 1.48–1.41 (m, 1H), 1.44 (s, 9H), 1.20 (s, 3H), 1.18 (s,
3H) ppm. 13C NMR (CDCl3, 75 MHz), d: 212.5 (C¼O), 167.9 (NꢀꢀC¼O),
154.6 (Nꢀꢀ (C¼O) ꢀꢀO), 80.1 (CꢀꢀO), 67.4 (C), 50.7 (C), 46.4 (CH2),
43.7 (CH2), 43.1 (CH), 42.3 (CH2), 28.4 (CH3), 27.4 (CH2), 27.1 (CH2),
21.3 (CH3), 21.0 (CH3) ppm. FTIR, m: 1740 (str), 1696 (str), 1633 (str)
cm21. MS (ESI), m/z (%): 723 ([2M123]1, 38), 373 ([M123]1, 100),
351 ([M11]1, 1). HRMS (ESI), m/z: 351.2273 (calcd for C19H30N2O4:
351.2278).
(1S,2R,4R)-1-[(4-Acetylpiperazin-1-yl)carbonyl]-7,7-dime-
thylnorbornan-2-ol (10).
A
two-necked round-bottom flask,
equipped with a magnetic stirrer and a water condenser was charged
with (1S,4R)-1-[(4-acetylpiperazin-1-yl)carbonyl]-7,7-dimethylnorbornan-
2-one [18(acetyl)], (0.15 g, 0.5 mmol), methanol (10 ml) and NaBH4
(1S,2R,4R)-1-{[4-(terc-Butoxycarbonyl)piperazin-1-yl]carbonyl}-
7,7-dimethylnorbornan-2-ol (11). (1S,4R)-1-{[4-(terc-Butoxycarbo-
nyl)piperazin-1-yl]carbonyl}-7,7-dimethylnorbornan-2-one [18(t-BOC)]
(0.15 g, 0.4 mmol) was reacted following the experimental procedure for
the preparation of 10. 0.13 g (92% yield). White solid. Mp: 207–2098C.
20
1
[a]D 212.8 (c 0.80, CHCl3). H NMR (CDCl3, 300 MHz), d: 4.17 (dd, J
5 7.8 Hz, J 5 3.8 Hz, 1H), 3.64–3.61 (m, 4H), 3.46–3.38 (m, 4H), 2.04–
1.75 (m, 5H), 1.63 (dd, J 5 4.2 Hz, J 5 4.2 Hz, 1H), 1.54–1.46 (m, 1H),
Fig. 1. Some efficient ligands for the addition of organozinc reagents to
aldehydes.
Chirality DOI 10.1002/chir

DUAL STEREOSELECTION IN THE ADDITION OF DIETHYLZINC
20
257
1.46 (s, 9H), 1.37 (s, 3H), 1.18–1.09 (m, 1H), 1.14 (s, 3H) ppm. 13C NMR
(CDCl3, 75 MHz), d: 172.3 (NꢀꢀC¼O), 155.0 (Nꢀꢀ (C¼O) ꢀꢀO), 80.6
(CꢀꢀO), 78.4 (CHꢀꢀOH), 61.1 (C), 51.0 (C), 45.2 (CH), 44.5 (CH2), 44.2
(CH2), 42.0 (CH2), 30.4 (CH2), 28,8 (CH3), 27.5 (CH2), 22.6 (CH3), 22.0
138–1408C. [a]D 27.7 (c 0.68, CHCl3). 1H NMR (CDCl3, 300 MHz), d:
4.15 (dd, J 5 7.8 Hz, J 5 3.7 Hz, 1H), 3.72–3.52 (m, 4H), 3.64 (t, J 5 5.5
Hz, 2H), 2.80–2.38 (m, 8H), 2.05–1.70 (m, 4H), 1.61 (t, J 5 4.3 Hz, 1H),
1.52–1.42 (m, 1H), 1.35 (s, 3H), 1.24–1.06 (m, 1H), and 1.12 (s, 3H) ppm.
13C NMR (CDCl3, 75 MHz), d: 171.7 (NꢀꢀC¼O), 77.8 (CHꢀꢀOH), 60.6
(C), 59.3 (CH2), 57.7 (CH2), 53.1 (CH2), 50.5 (C), 44.8 (CH), 44.0 (CH2),
41.4 (CH2), 29.9 (CH2), 27.0 (CH2), 22.1 (CH3), and 21.6 (CH3) ppm.
FTIR,m: 3383 (br., w), 1610 (str) cm21. MS (ESI), m/z (%): 297 ([M11]1,
100). HRMS (ESI), m/z: 297.2169 (calcd for C16H29N2O3, 297.2173).
(CH3) ppm. FTIR, m: 3425 (wide, w), 1688 (str), 1605 (str), 1236 (str) cm21
.
MS (ESI), m/z (%): 727 ([2M123]1, 100), 375 ([M11123]1, 31), 353
([M11]1, 2). HRMS (ESI), m/z: 353.2432 (calcd for C25H41N2O4, 353.2435).
Ligand 12:
(1S,4R)-1-{[4-(Ethylsulfonyl)piperazin-1-yl]carbonyl}-7,7-dime-
thylnorbornan-2-one [18(ethylsulfonyl)]. 1-(Ethylsulfonyl)pipera-
zine [17(ethylsulfonyl)] (0.32 g, 1.8 mmol) was reacted following the ex-
perimental procedure for the preparation of 18(acetyl). 0.47 g (86%
Ligand 14:
(1S,4R)-1-{[4-(2-Hydroxyphenyl)piperazin-1-yl]carbonyl}-
7,7-dimethylnorbornan-2-one [18(2-hydroxyphenyl)]. 1-(2-
Hydroxyphenyl)piperazine [17(2-hydroxyphenyl)] (0.32 g, 1.8 mmol)
was reacted following the experimental procedure for the preparation of
[18(2-hydroxyethyl)]. 0.52 g (84% yield). White solid. Mp: 138–1398C.
[a]D20 28.7 (c 0.30, CHCl3). 1H NMR (CDCl3, 300 MHz), d: 7.17 (dd, J 5
7.8 Hz, J 5 1.5 Hz, 1H), 7.10 (td, J 5 7.8 Hz, J 5 1.5 Hz, 1H), 6.96 (dd, J
5 7.8 Hz, J 5 1.5 Hz, 1H), 6.87 (td, J 5 7.8 Hz, J 5 1.5 Hz, 1H), 4.02 (br.
s, 1H), 3.76–3.38 (m, 3H), 3.07–2.75 (m, 4H), 2.54 (ddd, J 5 18.5 Hz, J 5
4.9 Hz, J 5 2.7 Hz, 1H), 2.38–2.28 (m, 1H), 2.17–2.00 (m, 3H), 1.94 (d, J
5 18.5 Hz, 1H), 1.52–1.43 (m, 1H), 1.25 (s, 3H), and 1.24 (s, 3H) ppm.
13C NMR (CDCl3, 75 MHz), d: 212.6 (C¼O), 167.8 (NꢀꢀC¼O), 151.3 (C),
138.3 (C), 126.7 (CH), 121.5 (CH), 120.1 (CH), 114.2 (CH), 67.4 (C), 52.8
(CH2), 50.7 (C), 43.7 (CH2), 43.1 (CH), 27.4 (CH2), 27.0 (CH2), 21.3
(CH3), and 21.0 (CH3) ppm. FTIR, m: 3351 (br., w), 1737 (str), 1624 (str)
cm21. MS (ESI-neg), m/z (%): 342 ([M1121]2, 27), 341 ([M21]2, 100).
HRMS (ESI-neg), m/z: 341.1874 (calcd for C20H25N2O3, 341.1871).
(1S,2R,4R)-1-{[4-(2-Hydroxyphenyl)piperazin-1-yl]carbonyl}-
yield). White solid. Mp. 163–1658C. [a]D 215.8 (c 1.22, CHCl3). 1H
20
NMR (CDCl3, 300 MHz), d: 3.77–3.04 (m, 8H), 2.95 (c, J 5 7.4 Hz, 2H),
2.50 (ddd, J 5 18.5 Hz, J 5 4.7 Hz, J 5 2.6 Hz, 1H), 2.30–2.17 (m, 1H),
2.15–1.95 (m, 3H), 1.91 (d, J 5 18.5 Hz, 1H), 1.51–1.41 (m, 1H), 1.36 (t, J
5 7.4 Hz, 3H), 1.19 (s, 3H), 1.18 (s, 3H) ppm. 13C NMR (CDCl3, 75 MHz),
d: 212.7 (C¼O), 167.8 (NꢀꢀC¼O), 67.4 (C), 50.7 (C), 46.1 (CH2), 43.8
(CH2), 43.6 (CH2), 43.1 (CH), 27.2 (CH2), 26.9 (CH2), 21.2 (CH3), 20.8
(CH3), 7.7 (CH3) ppm. FTIR, m: 1735 (str), 1616 (str), 1382 (str), 1117
(str) cm21. MS (ESI), m/z (%): 367 ([M12123]1, 3), 365 ([M123]1,
100). HRMS (ESI), m/z: 343.1698 (calcd for C16H27N2O4S: 343.1686).
(1S,2R,4R)-1-{[4-(Ethylsulfonyl)piperazin-1-yl]carbonyl}-
7,7-dimethylnorbornan-2-ol (12). (1S,4R)-1-{[4-(Ethylsulfonyl)pi-
perazin-1-yl]carbonyl}-7,7-dimethylnorbornan-2-one [18(ethylsulfonyl)]
(0.40 g, 1.2 mmol) was reacted following the experimental procedure for
the preparation of 10. 0.38 g (92% yield). White solid. Mp: 140–1418C.
20
1
[a]D 222.4 (c 1.40, CHCl3). H NMR (CDCl3, 300 MHz), d: 4.14 (dd, J
5 7.4 Hz, J 5 4.2 Hz, 1H), 3.81–3.66 (m, 4H), 3.37–3.22 (m, 4H), 2.95 (c,
J5 7.4 Hz, 2H), 2.04–1.75 (m, 5H), 1.65 (dd, J 5 4.2 Hz, J 5 4.2 Hz, 1H),
1.53–1.44 (m, 1H), 1.37 (s, 3H), 1.36 (t, J 5 7.4 Hz, 3H), 1.19–1.10 (m,
1H), 1.13 (s, 3H) ppm. 13C NMR (CDCl3, 75 MHz), d: 171.8 (NꢀꢀC¼O),
78.2 (CHꢀꢀOH), 60.6 (C), 50.6 (C), 45.9 (CH2), 44.7 (CH), 44.2 (CH2),
43.9 (CH2), 41.8 (CH2), 30.0 (CH2), 26.9 (CH2), 22.1 (CH3), 21.6 (CH3),
7.7 (CH3) ppm. FTIR, m: 3452 (wide, w), 1624 (str), 1282 (str), 1184 (str)
cm21. MS (ESI), m/z (%): 369 ([M12123]1, 3), 367 ([M123]1, 100).
HRMS (ESI), m/z: 367.1661 (calcd for C16H28N2NaO4S, 367.1662).
7,7-dimethylnorbornan-2-ol
(14). (1S,4R)-1-{[4-(2-Hydroxyphe-
nyl)piperazin-1-yl]carbonyl}-7,7-dimethylnorbornan-2-one [18(2-hydrox-
yphenyl)] (0.34 g, 1.0 mmol) was reacted following the experimental
procedure for the preparation of 10. 0.29 g (81% yield). White solid. Mp:
149–1508C. [a]D 29.8 (c 0.24, CHCl3). 1H NMR (CDCl3, 300 MHz), d:
20
7.10 (td, J 5 7.6 Hz, J 5 1.4 Hz, 2H), 6.97 (dd, J 5 7.6 Hz, J 5 1.4 Hz,
1H), 6.87 (td, J 5 7.6 Hz, J 5 1.4 Hz, 1H), 4.21 (dd, J 5 7.8 Hz, J 5 3.7
Hz, 1H), 3.89–3.77 (m, 4H), 2.95–2.82 (m, 4H), 2.11–1.78 (m, 5H), 1.67
(t, J 5 4.3 Hz, 1H), 1.59–1.51 (m, 1H), 1.42 (s, 3H), 1.34–1.24 (m, 1H),
and 1.19 (s, 3H) ppm. 13C NMR (CDCl3, 75 MHz), d: 171.9 (NꢀꢀC¼O),
151.3 (C), 138.2 (C), 126.9 (CH), 121.4 (CH), 120.2 (CH), 114.4 (CH),
78.1 (CHꢀꢀOH), 60.8 (C), 52.8 (CH2), 50.7 (C), 44.9 (CH2), 44.8 (CH),
41.6 (CH2), 30.1 (CH2), 27.1 (CH2), 22.2 (CH3), 21.7 (CH3) ppm. FTIR,m:
3383 (br., w), and 1592 (str) cm21. MS (ESI-neg), m/z (%): 344
([M1121]2, 18), 343 ([M21]2, 100). HRMS (ESI-neg), m/z: 343.2029
(calcd for C20H27N2O3, 343.2027).
Ligand 13:
(1S,4R)-1-{[4-(2-Hydroxyethyl)piperazin-1-yl]carbonyl}-7,7-
dimethylnorbornan-2-one [18(2-hydroxyethyl)]. In a round-bot-
tom flask equipped with a magnetic stirrer, 4-(hydroxyethyl)piperazine
[17(2-hydroxyethyl)] (0.23 g, 1.8 mmol) was dissolved in dry THF (4
ml) under argon. Then, triethylamine (0.35 g, 3.5 mmol) was added, fol-
lowed by ketopinic acid chloride19 (0.36 g, 1.8 mmol) in dry THF (1 ml).
The reaction mixture was refluxed for 24 h. After cooling it down to
room temperature, the mixture was filtrated in vacuo. The residue was
dissolved in CHCl3 (10 ml), water (10 ml) was added and the phases sep-
arated. The organic phase was washed with 10% NaOH (1 3 10 ml),
water (1 3 10 ml), and brine (1 3 10 ml) and dried with anhydrous
Na2SO4. After filtration and solvent evaporation under reduced pressure,
the residue was purified by flash column chromatography (silica gel,
hexane/ethyl acetate; 0.47 g, 89% yield). White solid. Mp: 93–948C.
Ligand 15:
(1S,4R)-1-{[4-(3-Hydroxyphenyl)piperazin-1-yl]carbonyl}-7,7-
dimethylnorbornan-2-one [18(3-hydroxyphenyl)]. 1-(3-Hydroxy-
phenyl)piperazine [17(3-hydroxyphenyl)] (0.32 g, 1.8 mmol) was
reacted following the experimental procedure for the preparation of
[18(2-hydroxyethyl)]. 0.52 g (84% yield). White solid. Mp: 64–658C.
[a]D20 212.1 (c 0.40, CHCl3). 1H NMR (CDCl3, 300 MHz), d: 7.12 (t, J 5
8.1 Hz, 1H), 6.49 (dd, J 5 8.1 Hz, J 5 1.9 Hz, 1H), 6.40 (t, J 5 1.9 Hz,
1H), 6.37 (dd, J 5 8.1 Hz, J 5 1.9 Hz, 1H), 5.60 (br. s, 1H), 3.66–3.55 (m,
4H), 3.28–3.11 (m, 4H), 2.54 (ddd, J 5 18.4 Hz, J 5 4.9 Hz, J 5 2.8 Hz,
1H), 2.41–2.28 (m, 1H), 2.21–2.01 (m, 3H), 1.95 (d, J 5 18.4 Hz, 1H),
1.52–1.43 (m, 1H), 1.25 (s, 3H), and 1.24 (s, 3H) ppm. 13C NMR (CDCl3,
75 MHz), d: 212.7 (C¼O), 167.8 (NꢀꢀC¼O), 157.3 (C), 152.4 (C), 130.0
(CH), 108.4 (CH), 107.4 (CH), 103.5 (CH), 67.5 (C), 50.7 (C), 49.5
(CH2), 43.7 (CH2), 43.2 (CH), 27.5 (CH2), 27.0 (CH2), 21.3 (CH3), 21.0
(CH3) ppm. FTIR,m: 3317 (br, w), 1738 (str), and 1607 (str) cm21. MS
(ESI), m/z (%): 343 ([M11]1, 100). HRMS (ESI), m/z: 343.2018 (calcd
for C20H27N2O3, 343.2016).
20
1
[a]D 215.1 (c 0.77, CHCl3). H NMR (CDCl3, 300 MHz), d: 3.79 (br. s,
1H), 3.62 (t, J 5 5.4 Hz, 2H), 3.58–3.40 (m, 3H), 2.65–2.45 (m, 5H), 2.55
(t, J 5 5.4 Hz, 2H), 2.31–2.21 (m, 1H), 2.16–1.90 (m, 3H), 1.89 (d, J 5
18.4 Hz, 1H), 1.48–1.38 (m, 1H), 1.24–1.07 (m, 1H), 1.20 (s, 3H), 1.19 (s,
3H) ppm. 13C NMR (CDCl3, 75 MHz), d: 212.5 (C¼O), 167.5 (NꢀꢀC¼O),
67.4 (C), 59.2 (CH2), 57.7 (CH2), 53.0 (CH2), 50.6 (C), 43.7 (CH2), 43.1
(CH), 27.4 (CH2), 27.0 (CH2), 21.3 (CH3), 20.9 (CH3) ppm. FTIR, m: 3423
(br, w), 1739 (str), 1626 (str), 997 (str) cm21. MS (ESI-neg), m/z (%):
294 ([M1121]2, 14), 293 ([M21]2, 100). HRMS (ESI-neg), m/z:
293.1897 (calcd for C16H28N2NaO4S, 293.1871).
(1S,2R,4R)-1-{[4-(2-Hydroxyethyl)piperazin-1-yl]carbonyl}-
7,7-dimethylnorbornan-2-ol (13). (1S,4R)-1-{[4-(2-Hydroxyethyl)-
(1S,2R,4R)-1-{[4-(3-Hydroxyphenyl)piperazin-1-yl]carbonyl}-
7,7-dimethylnorbornan-2-ol (15). (1S,4R)-1-{[4-(3-hydroxyphenyl)-
piperazin-1-yl]carbonyl}-7,7-dimethylnorbornan-2-one
[18(2-hydrox-
piperazin-1-yl]carbonyl}-7,7-dimethylnorbornan-2-one
[18(3-hydroxy-
yethyl)] (0.29 g, 1.0 mmol) was reacted following the experimental pro-
cedure for the preparation of 10. 0.20 g (70% yield). White solid. Mp:
phenyl)] (0.34 g, 1.0 mmol) was reacted following the experimental pro-
cedure for the preparation of 10. 0.27 g (79% yield). White solid. Mp:
Chirality DOI 10.1002/chir

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SANCHEZ-CARNERERO ET AL.
258
205–2068C. [a]D 26.1 (c 0.59, CHCl3). 1H NMR (CDCl3, 300 MHz), d:
7.04 (t, J 5 8.1 Hz, 1H), 6.46 (dd, J 5 8.1 Hz, J 5 2.0 Hz, 1H), 6.41 (t, J
5 2,0 Hz, 1H), 6.32 (dd, J 5 8.1 Hz, J 5 2.0 Hz, 1H), 4.28 (dd, J 5 7.7
Hz, J 5 3.7 Hz, 1H), 3.89–3.65 (m, 4H), 3.22–2.99 (m, 4H), 2.00–1.75 (m,
4H), 1.70–1.62 (m, 1H), 1.55 (t, J 5 4.2 Hz, 1H), 1.38 (s, 3H), 1.28–1.15
(m, 1H), and 1.13 (s, 3H) ppm. 13C NMR (CDCl3, 75 MHz), d: 173.8
(NꢀꢀC¼O), 159.2 (C), 153.9 (C), 130.8 (CH), 109.1 (CH), 108.4 (CH),
104.7 (CH), 78.2 (CHꢀꢀOH), 61.7 (C), 51.5 (C), 50.7 (CH2), 46.5 (CH),
45.1 (CH2), 42.6 (CH2), 31.0 (CH2), 28.0 (CH2), 22.7 (CH3), and 22.2
(CH3) ppm. FTIR, m: 3310 (br., w), 1604 (str) cm21. MS (ESI), m/z (%):
345 ([M11]1, 100). HRMS (ESI), m/z: 345.2161 (calcd for C20H29N2O3,
345.2173).
20
Ligand 27:
(1S,4R)-1-{[4-(2-Methoxyethyl)piperazin-1-yl]carbonyl}-7,7-
dimethylnorbornan-2-one [18(2-methoxyethyl)]. 1-(2-Methox-
yethyl)piperazine [17(2-methoxyethyl)] (0.26 g, 1.8 mmol) was reacted
following the experimental procedure for the preparation of [18(2-
Fig. 3. Chosen ligands for the proposed screening.
mide) is extremely close, which indicates that the nonprotic
amino group of the 4-methylpiperazine moiety does not par-
ticipate in the catalytic activity of the corresponding aminohy-
droxyamide.21 In this context, we decided to check the cata-
lytic activity of a set of piperazine-based ketopinic-acid
derived hydroxy(diamides) (10–12 in Fig. 3) and amino(di-
hydroxy)amides (13–15 in Fig. 3), which are closely related
to the highly efficient bis(hydroxyamide) 3 and also easily
obtainable from both commercial (1S)-ketopinic acid and 1-
substituted piperazines, to know if the new structural varia-
tions introduced in the parent ligand could produce some
noticeably switch in the stereoselection sense.
20
hydroxyethyl)]. 0.53 g (95% yield). Pale brown oil. [a]D 218.8 (c 0.68,
1
CHCl3). H NMR (CDCl3, 300 MHz), d: 6.00 (br. s, 1H)), 3.51 (t, J 5 5.5
Hz, 4H), 3.34 (s, 3H), 2.70–2.44 (m, 5H), 2.59 (t, J 5 5.5 Hz, 2H), 2.36–
2.22 (m, 1H), 2.13–1.81 (m, 4H), 1.89 (d, J 5 18.4 Hz, 1H), 1.47–1.38 (m,
1H), 1.20 (s, 3H), and 1.19 (s, 3H) ppm. 13C NMR (CDCl3, 75 MHz), d:
212.4 (C¼O), 167.4 (NꢀꢀC¼O), 69.8 (CH2), 67.3 (C), 58.8 (CH3), 57.7
(CH2), 53.7 (CH2), 50.6 (C), 43.7 (CH2), 43.1 (CH), 27.4 (CH2), 27.1
(CH2), 21.3 (CH3), and 21.0 (CH3) ppm. FTIR,m: 3537 (br, w), 1739 (str),
1629 (str) cm21. MS (ESI), m/z (%): 309 ([M11]1, 100). HRMS (ESI),
m/z: 309.2169 (calcd for C17H29N2O3, 309.2173).
(1S,2R,4R)-1-{[4-(2-Methoxyethyl)piperazin-1-yl]carbonyl}-
7,7-dimethylnorbornan-2-ol (27). (1S,4R)-1-{[4-(2-Methoxyethyl)-
piperazin-1-yl]carbonyl}-7,7-dimethylnorbornan-2-one
[18(2-methox-
The ligand set has been chosen as follows: on the one
hand, ligand 10 is a structural simplification of 3, where one
chiral b-hydroxyacyl moiety of the latter has been substi-
tuted for a simple achiral acyl (acetyl) moiety in the former.
Therefore, the new ligand 10 keeps the two amide groups of
parent 3, but lacks one hydroxyl function. In ligands 11 and
12, analogous to 10, the coordinative ability of the acyl
group has been modified by substituting it by an (alkyloxy)-
carbonyl in the case of 11 or by an alkylsulfonyl in the case
of 12 (cf., ligands 3, 10, 11, and 12 in Figs. 1 and 3).
On the other hand, ligands 13 and 14 are also simplifica-
tions of 3, but now, one chiral b-hydroxyacyl moiety of the
latter has been substituted for a simple b-hydroxyalkyl or b-
hydroxyaryl moiety in the former ones. Therefore, new
ligands 13 and 14 keep the two hydroxyl functions of parent
3, but change one amide function for a nonprotic amine.
Finally, ligand 15 is a positional isomer of 14, where the
new hydroxyl group has been distanced from the other func-
tional groups (cf., ligands 3, 13, 14, and 15 in Figs. 1 and 3).
All the chosen ligands were straightforwardly prepared
(see yields in the experimental part) by amidation of (1S)-
ketopinic acid (16) with the corresponding commercial
1-substituted piperazine 17(Z),* followed by a chemo- and
highly stereoselective reduction of the obtained norborna-
none-based amide 18(Z) with sodium borohydride, as shown
in Scheme 2. The catalytic activity of ligands 10–15 was
tested in the addition of diethylzinc to benzaldehyde. Table 1
shows the obtained results.
yethyl)] (0.34 g, 1.1 mmol) was reacted following the experimental pro-
cedure for the preparation of 10. 0.27 g (79% yield). White solid. Mp:
89–918C. [a]D 245.7 (c 0.21, CHCl3). 1H NMR (CDCl3, 300 MHz), d:
20
4.16 (dd, J 5 7.8 Hz, J 5 3.8 Hz, 1H), 3.70 (t, J 5 4.8 Hz, 4H), 3.53 (t, J
5 5.4 Hz, 2H), 3.36 (s, 3H), 2.61 (t, J 5 5.4 Hz, 2H), 2.55–2.44 (m, 4H),
2.05–1.74 (m, 5H), 1.63 (t, J 5 4.4 Hz, 1H), 1.54–1.45 (m, 1H), 1.37 (s,
3H), 1.28–1.06 (m, 1H), 1.15 (s, 3H) ppm. 13C NMR (CDCl3, 75 MHz), d:
171.6 (NꢀꢀC¼O), 77.9 (CHꢀꢀOH), 69.9 (CH2ꢀꢀOH), 60.7 (C), 58.9
(CH3), 57.7 (CH2), 53.7 (CH2), 50.5 (C), 44.8 (CH), 44.0 (CH2), 41.2
(CH2), 29.9 (CH2), 27.1 (CH2), 22.2 (CH3), 21.5 (CH3) ppm. FTIR, m:
3427 (br., w), 1613 (str.), 1427 (str) cm21. MS (ESI), m/z (%): 311
([M11]1, 100). HRMS (ESI), m/z: 311.2320 (calcd for C17H31N2O3,
311.2330).
Asymmetric Reaction
Typical procedure Into a 10-ml round-bottom flask, equipped with
a magnetic stirrer under argon and containing the corresponding ligand
(0.02 mmol), diethylzinc solution (1.10 mmol, 1.0 M in hexanes) was
added at room temperature. The mixture was stirred at room tempera-
ture for 5 min. Benzaldehyde (1.0 mmol) was then added and the reac-
tion mixture was stirred at room temperature for 5 h. The reaction was
quenched by the addition of 10% HCl (3 ml). The resulting mixture was
extracted with ether (3 3 3 ml). The combined organic layers were sub-
mitted to celite filtration and solvent evaporation. The obtained residue
was dissolved in HPLC-grade hexanes and submitted to analysis by GC
and chiral HPLC.
RESULTS AND DISCUSSION
In our previous studies on how structural variations could
affect the catalytic activity of ketopinic-acid derived hydroxya-
mides in the enantioselective addition of diethylzinc to benz-
aldehyde, we demonstrated that bis(hydroxyamides) having
diamine spacers based on piperazine are more efficient than
related simple hydroxyamides or tris(hydroxyamides).20,21
Moreover, the catalytic activity of 4-methylpiperazine- and pi-
peridine-based ligands (aminohydroxyamide vs. hydroxya-
*For the acylation of aminoamides 17(Z) (Z being acetyl, t-BOC and ethylsul-
fonyl) with ketopinic acid, EDC was used as the acid activator (procedure A
in Scheme 1). However the corresponding N-acylation of hydroxydiamines
17(Z) (Z being 2-hydroxyethyl, 2-hydroxyphenyl and 3-hydroxyphenyl) under
the same conditions took place with very low yield. Nevertheless, the desired
hydroxyaminoamides could be obtained by using ketopinoyl chloride as the
acid activated specie (procedure B in Scheme 1).
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DUAL STEREOSELECTION IN THE ADDITION OF DIETHYLZINC
259
Fig. 4. Some previously reported ketopinic-acid derived hydroxyamide-
based O/O ligands (in parentheses ee and sense of the stereoselection for
benzaldehyde ethylation).
Scheme 2. Preparation of the chosen ligands.
On the contrary, the high variation in the catalytic activity
reached with the amino(dihydroxy)amides 13–15 (from 66%
ee pro-S to 66% ee pro-R, see Table 1), shows a clear participa-
tion of the variable structural moiety, that is, the hydrox-
yalkyl or hydroxyaryl moiety, in such activity. Moreover, the
pro-S stereoselection exerted by ligand 13, instead of the
common pro-R one exerted by all the previous reported (1S)-
ketopinic-acid derived isoborneol-based hydroxyamides, con-
stitutes the first example of dual stereoselection for this
interesting type of ligands (73% dual switch, with 156 points
of ee switch, for the ligand couple 3/13; values calculated
from the data in Table 1). Strikingly, the ligand couple 13/
14, which is formed by highly structurally close individuals,
shows a noticeably strong dual stereoselection (100% dual
switch, with 132 points of ee, values calculated from the data
in Table 1).
We explain the behavior of the tested amino(dihydroxy)a-
mides 13–14, as well as the found striking dual stereoselec-
tion, by participation of both hydroxyl groups in the catalytic
activity, through the formation of the catalytic zinc dialkoxide
21 (Fig. 5), like the zinc dialkoxides were proposed previ-
ously for bis(hydroxyamides) (22 in Fig. 5).15,20,21 We also
propose for 21 a chelation of the zinc centre by the amide
oxygen atom, but not by the amine nitrogen. This proposed
chelation is based on the well-established participation of
such oxygen in the catalytic activity of all the reported iso-
borneol-based ketopinic-acid derived hydroxyamides,15,20,21
The ees reached with the new ligands were lower to that
reached with bis(hydroxyamide) 3 (Table 1). These results
demonstrate the importance of the four functional groups of
the latter (two carboxamides and two hydroxyls) in its cata-
lytic activity, which is in agreement with the zinc-chelate cat-
alyst proposed previously by us for bis(hydroxyamides)
(acting as O/O/O/O tetradentated ligands).15,20,21 More-
over, the catalytic activity exerted by the hydroxy(diamides)
10–12 (72–78% ee pro-R) was very similar to that exerted by
simple piperidine-based hydroxyamides20 or piperazine-
based aminohydroxyamides21 (e.g., 72% ee pro-R for 19 or
74% ee for 20 in Fig. 4). This fact indicates that the additional
nonprotic amide group of piperazine-based hydroxy(dia-
mides) 10–12 does not participate (simple O/O bidentated
ligands), as previously demonstrated for the additional non-
protic amino group in piperazine-based aminohydroxyamides
(Fig. 4).21
TABLE 1. Catalytic activity of ligands 10–15 in enantioselec-
tive addition of diethylzinc to benzaldehydea
Ligand
1-Phenylpropan-1-ol
Yield (%)b
ee (%)c
Configurationc
3d
10
11
12
13
14
15
97
91
97
79
99
99
92
99
99
93
90
72
78
74
66
66
62
4
R
R
R
R
S
R
R
R
R
R
18(2-Hydroxyethyl)
18(2-Hydroxyphenyl)
27
8
78
Previous results for ligand 3 are included for comparison.
a2.0 mol equiv. of Et2Zn (1.0 M in hexanes); 0.05 mol equiv. of ligand; t 5 5
h; T 5 r.t.
bDetermined by GC.
cDetermined by chiral HPLC (Chiralpak IC). Both elution peaks were previ-
ously assigned from a known mixture of enantiomers, in which the configura-
tion for the major isomer was also known on the basis of the sign of the mix-
ture’s optical rotation.
dData previously reported in references 15, 19, and 20.
Fig. 5. Proposed catalyst models.
Chirality DOI 10.1002/chir

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SANCHEZ-CARNERERO ET AL.
260
and also on the established nonexistent participation of the
nonprotic amine piperazine in the catalytic activity of analo-
gous ligands based on 1-substituted piperazine (e.g. 20 in
Fig. 4).21 Thus, whereas bis(hydroxyamides) act as tetraden-
tated O/O/O/O ligands (see 22), amino(dihydroxy)amides
would act as tridentated O/O/O ones (see 21).
For ligands 13 and 14 a bis(zinc-chelate) catalyst of the
type of 23 (Fig. 5) would be possible, in which the amino(di-
hydroxy)amide ligand would act as the sum of two independ-
ent and competing hydroxyamide and amino-alcohol ligands.
However, we have discarded this possibility because, if this
was the case, the activity would be mainly controlled by the
expected higher activity of the amino-alcohol-based chelate,
giving place to a low ee due to its remoteness from the ligand
stereocentres. To support this hypothesis, we have tested
the catalytic activity of the norbornanone-based precursors of
13 and 14 (i.e., 18(Z) with Z 5 2-hydroxyethyl or 2-hydrox-
yphenyl, see Scheme 2), where the action of an active low-
stereodifferentiating amino-alcohol-based chelate, analogue
to that depicted in 23, should be predominant. The results
obtained from testing the mentioned ligands 18(Z), in the
same conditions used for 13 and 14 (Table 1), show a high
catalytic activity (high reaction yields), but with a low stereo-
differentiation (4–8% ee), in agreement with our hypothesis.
Conversely, whereas in catalyst 22 both catalytic oxides
are equal, leading to a favored ‘‘endo/anti/anti’’ pro-R transi-
tion state 24 (Fig. 6),15,20 in 21 are not. Thus, for catalyst
21, the coordination through the norbornane alkoxide (ox-
Fig. 7. Analogue of ligand 13, lacking the key pro-S hydroxyl group.
ide 1 in Fig. 5) would lead to a favored endo/anti/anti pro-R
transition state 25, whereas the other competing oxide (ox-
ide 2 in Fig. 5) would lead to a favored endo/anti/anti pro-S
transition state 26 (Fig. 6).
This pro-R/pro-S dual activity of catalyst 21 explains the
lower pro-R activity of the amino(dihydroxy)amides 13–15
when compared to other ketopinic-acid derived hydroxya-
mides (Table 1). Moreover, the activity of catalyst 21 must
be modulated by the relative activity of both competing cata-
lyst oxides, which explains the dual stereoselection found for
the couple 13/14. Thus, for pro-S ligand 13, both oxides of
the corresponding catalyst 21 are alkoxides: a pro-R oxide 1
based on nobornanol and a pro-S oxide 2 based on ethanol
(Figs. 3 and 5). The expected higher activity for oxide 2, due
to its less sterical hindrance to the reactive-diethylzinc coor-
dination (activation), explains the found experimental pro-S
stereoselection of ligand 13. On the contrary, for the corre-
sponding catalyst 21 derived from pro-R ligand 14 (and also
from ligand 15), where the pro-S oxide 2 is a phenoxide
(Figs. 3 and 5), the less coordinative ability of phenoxides
when compared to alkoxides would explain the found experi-
mental pro-R stereoselection.
Finally, we have synthesized and tested ligand 27 (Fig. 7)
to support the solidness of our empiric models of catalysts
and controlling transition states for the studied ketopinic-
acid ligands. Ligand 27 is an analogue of ligand 13, in
which the key pro-S hydroxyl group of the latter has been
changed for a nonprotic methoxyl. Therefore, for this new
ligand the common pro-R behavior of the simple ketopinic-
acid derived hydroxyamide-based O/O ligands (Fig. 4) must
be expected.
The synthesis of 27 was straightforwardly realized (see
experimental part) according to the standard route (proce-
dure B) shown in Scheme 2, but starting from commercial 2-
(methoxyethyl)piperazine instead (17(Z) with Z 5 2-methox-
yethyl). The catalytic test (ethylation of benzaldehyde) was
also realized under the standard conditions (Table 1), the
obtained result demonstrating (78% ee pro-R) the reliability of
the proposed models.
CONCLUSIONS
Readily accessible (1S)-ketopinic-acid derived hydroxya-
mides based on hydroxyalkyl or hydroxyaryl piperazine [i.e.,
amino(dihydroxy)amides] are able to promote the enantiose-
lective addition of diethylzinc to benzaldehyde as other
ligands belonging to the same interesting hydroxyamide-
based typology do. However, the sense of the stereoselection
exerted by these new ligands can be easily switched by tun-
ing the coordinative ability of the additional hydroxyl group
of the piperazine moiety. An explanation to this fact is given
on the basis of the formation of an acting zinc-dialkoxide cat-
alyst with two different catalytic centres for the diethylzinc
activation, a pro-R zinc-oxide centre versus a pro-S one. This
Fig. 6. Proposed favored transitions states from catalysts 22 and 21.
Chirality DOI 10.1002/chir

DUAL STEREOSELECTION IN THE ADDITION OF DIETHYLZINC
261
12. Chen YK, Jeon SJ, Walsh PJ, Nuggent WA. (2S)-(–)-3-exo-(Morpholino)i-
fact allows the establishment of an effective dual stereoselec-
tion in highly structurally close ligands obtained by similar
synthetic routes with similar economic costs, which enhan-
ces the interest of the sustainable ketopinic-acid derived
hydroxyamides.
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Chirality DOI 10.1002/chir