Asymmetric addition of dimethylzinc to alkylidenmalonates mediated by phosphorous ligands: A new synthetic route to floral fragrances

Article abstract of DOI:10.1002/chir.20987

Six new phosphite ligands were prepared and their efficiency as chiral ligands was investigated in the copper-catalyzed asymmetric conjugate addition of dimethylzinc to diethyl 3-phenylpropylidenmalonate (5), affording the addition product with ees up to 74%. Moreover, a simple and straightforward route to floral fragrances Phenoxanol, Citralis, and Nitrile Citralis in optically active form through the above cited reaction was proposed. Chirality, 2011. 2011 Wiley-Liss, Inc. Copyright

Full text of DOI:10.1002/chir.20987

CHIRALITY 23:761–767 (2011)
Asymmetric Addition of Dimethylzinc to Alkylidenmalonates
Mediated by Phosphorous Ligands: A New Synthetic
Route to Floral Fragrances
*
*
STEFANO SUPERCHI, VALERIA MARCHITIELLO, LAURA PISANI, AND PATRIZIA SCAFATO
Dipartimento di Chimica ‘‘A. M. Tamburro,’’ Universita` della Basilicata, via dell’Ateneo Lucano, 10, Potenza 85100, Italy
Contribution to the Carlo Rosini Special Issue
ABSTRACT
Six new phosphite ligands were prepared and their efficiency as chiral ligands
was investigated in the copper-catalyzed asymmetric conjugate addition of dimethylzinc to
diethyl 3-phenylpropylidenmalonate (5), affording the addition product with ees up to 74%.
Moreover, a simple and straightforward route to floral fragrances Phenoxanol, Citralis, and
Nitrile Citralis in optically active form through the above cited reaction was proposed. Chirality
C
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23:761–767, 2011.
2011 Wiley-Liss, Inc.
KEY WORDS: asymmetric conjugate addition; phosphorous ligands; chiral esters; Phenoxanol;
Citralis; Nitrile Citralis
INTRODUCTION
dure. In fact, the asymmetric conjugate addition of dimethyl-
zinc to unsaturated compounds can be a very direct method
to obtain a methyl-substituted stereogenic center, a struc-
tural motif that often plays an important role in determining
the biological activity of numerous natural compounds. In
particular, we focused our attention on the development of
new synthetic approaches for the preparation in optically
active form of some valuable fragrances such as 3-methyl-5-
phenyl-pentanol (Phenoxanol) and the structurally related
fragrances 3-methyl-5-phenyl-pentanaldehyde (Citralis) and
3-methyl-5-phenyl-pentanenitrile (Nitrile Citralis)13,14 (Scheme 1),
choosing 3-phenylpropylidenmalonate (5) as starting sub-
strate on which to test the asymmetric addition.
These three synthetic fragrances posses floral and fruity
notes (rose, lily-of-the-valley, citrus) and are commercially
available in racemic form. An efficient asymmetric synthesis
of Phenoxanol, as well as its transformation in Citralis and
Nitrile Citralis, was reported by Matteoli14 who also reported
the odor profiles of the single enantiomers, showing a signifi-
cant difference in odor threshold between compounds with
opposite configuration and, for Phenoxanol, also in olfactorily
notes. Such a synthetic procedure was based on the asymmet-
ric hydrogenation of (Z)- or (E)-allylic alcohols with Ru-2,20-
bis(diphenylphosphino)-1,10-binaphtalene (BINAP) complexes
giving products in high enantiomeric excesses, but requiring
high hydrogen pressure (100 atm) and long reaction times
(48 h) for the complete conversion. On the other hand, we
propose, herein, a new and mild access to Phenoxanol based
on the asymmetric addition of dimethylzinc to 3-phenylpropy-
lidenmalonate, in turn easily achievable by Knoevenagel
reaction from inexpensive chemicals, followed by deethoxy-
carbonilation and reduction of the optically active ester.
The copper-catalyzed conjugate addition of organozinc
reagents to a,b-unsaturated carbonyl compounds is a
widely used strategy for the catalytic asymmetric CꢀꢀC
bond formation. To this end, different types of a,b-unsatu-
rated ketones and nitroalkenes have been used1–4 as well
as, more recently, sulfones5,6 and aldehydes.7 In the latter
case, good enantioselectivity was achieved but with moder-
ate to good 1–4 regioselectivity in comparison with the com-
petitive 1–2 addition and the aldol reaction. Acyclic a,b-un-
saturated esters are generally not reactive toward dialkyl-
zinc reagents, but a few examples have been reported about
the asymmetric conjugate addition of Grignard reagents to
a,b-unsaturated esters with Cu-ferrocenylphosphines8 or
Cu-2,20-bis(di-p-tolylphosphino)-1,10-binaphthalene (CuTolyl-
BINAP)9 complexes. In the first case, good yields and enan-
tiomeric excesses were obtained with several Grignard
reagents but not with methylmagnesium bromide, which
instead gave good conversions and excellent enantioselec-
tivities when Tolyl-BINAP was used as ligand. These results
are particularly interesting due to the remarkable impor-
tance of chiral 3-alkylsubstituted esters, as well as corre-
sponding alcohols and acids, both in asymmetric synthesis
and as precursors of biologically active compounds.
Although several Grignard reagents are commercially avail-
able and inexpensive, dialkylzinc reagents offer however
some advantages because of their better tolerance toward
several functional groups.10 An indirect method to obtain
optically active 3-methylesters by copper-catalyzed conju-
gate addition of diorganozinc reagents was developed by
Feringa and coworkers,11 who reported an efficient asym-
metric addition of dimethylzinc to alkylidenmalonates in the
presence of phosphoramidite ligands. The addition products
in fact can be easily transformed in 3-alkyl substituted
monoesters by direct dealkoxycarbonylation.12
Contract grant sponsors: MIUR-PRIN 2008LYSEBR and Universita` della Basi-
licata (Potenza).
*Correspondence to: Dr. Patrizia Scafato, Dipartimento di Chimica ‘‘A. M.
Tamburro,’’ Universita` della Basilicata, Via dell’Ateneo Lucano, 10, Potenza
85100, Italy. E-mail: patrizia.scafato@unibas.it
Received for publication 10 May 2011; accepted in revised form 12 May 2011;
Accepted 17 May 2011
DOI: 10.1002/chir.20987
We decided to explore, herein, the behavior of a variety of
phosphorous ligands in the copper-catalyzed asymmetric
addition of dimethylzinc to 3-phenylpropylidenmalonate with
the aim to disclose new synthetic applications of this proce-
Published online 17 August 2011 in Wiley Online Library
(wileyonlinelibrary.com).
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2011 Wiley-Liss, Inc.

762
SUPERCHI ET AL.
Scheme 1. Synthetic scheme to Phenoxanol, Citralis, and Nitrile Citralis.
NMR (400 MHz, CDCl3), d (ppm): 5.00 (d, J 5 8.1 Hz, 1H), 5.03 (d, J 5
8.1 Hz, 1H), 6.59 (s, 1H), 7.327.5 (m, 10H), 7.51 (t, J 5 3.1 Hz, 1H), 7.54
(t, J 5 3.1 Hz, 1H), 7.8 (dd, J1 5 8.4 Hz, J2 5 1.4 Hz, 1H), 7.928.0 (m,
3H), 8.12 (s, 1H); 13C NMR (100 MHz, CDCl3), d (ppm): 86.44, 86.91,
107.00, 125.32, 126.74, 127.07, 127.32, 127.63, 127.81, 128.54, 131.00,
133.00, 135.03, 136.41.
EXPERIMENTAL
General Procedures
1H (400 MHz) and 13C (100 MHz) NMR spectra were recorded in
CDCl3 on a Varian INOVA 400 spectrometer, using tetramethylsilane
(TMS) as an internal standard. 31P (162 MHz) NMR spectra were
recorded in CDCl3 on a Varian INOVA 400 spectrometer, using triphe-
nylphosphate (CDCl3, 217.7 ppm) as an external standard. GC–MS
spectra were recorded on a Hewlett Packard 6890 gas chromatograph,
equipped with a mass spectrometric detector HP-5973 type and a capil-
lary column HP-5MS 30 m 3 0.25 mm. Melting points were taken using
a Kofler Reichert-Jung thermovar apparatus and are uncorrected. Optical
rotations were measured with a JASCO DIP-370 digital polarimeter.
HPLC analyses were performed on a JASCO PU-1580 intelligent HPLC
pump equipped with a Varian 2550 UV detector and CHIRALCEL OJ-H
column. Thin layer chromatography (TLC) analyses were performed on
silica gel 60 Macherey-Nagel sheets, flash chromatography separations
were carried out using silica gel 60 (70–230 mesh). Toluene was distilled
over sodium-benzophenone, whereas dichloromethane and chloroform
were distilled over calcium hydride prior their use. DIBALH (Aldrich)
was a 1.5 M solution in toluene, Me2Zn (Aldrich) was a 2 M solution in
toluene, MeMgBr (Aldrich) was a 3 M solution in Et2O. PCl3 was dis-
tilled, under nitrogen, before its use. Et3N was distilled over calcium
hydride, under nitrogen, before its use. N,N-Dimethylaminopyridine
(DMAP) and (R)- and (S)-1,1’-bi(2-naphtol) (BINOL) were dried heating
at 508C at reduced pressure, for 5 h, before the use. Preparation of (S)-
L1,15,16 (aR,R,R)-L2a,17 (aS,R,R)-L3a,17 (R,R)-9a,18 (R,R)-10a,18 (R,R)-
9d,19 and (R,R)-10d19 has been described elsewhere. Diethyl 3-phenyl-
propylidenemalonate (5) was prepared in 43% yield according to litera-
ture procedure11 starting from 3-phenylpropionaldehyde. Enantiopure
(R,R)-1,2-diphenylethane-1,2-diol (8a)20 and (R,R)-1,2-di(2-naphthyl)-
ethane-1,2-diol (8b)21 were prepared according to literature procedures.
(4R,5R)-4,5-Di(naphthalen-2-yl)-2-phenyl-1,3-dioxolane (9e). Yield
86% (pale yellow solid); m.p. 5 112–1158C; [a]20D 5 165.2 (c 1.06, CHCl3);
1H NMR (400 MHz, CDCl3) d (ppm): 5.25 (s, 2H), 6.58 (s, 1H), 7.44–7.58
(m, 8H), 7.76–7.78 (m, 6H), 7.87–7.92 (m, 5H); 13C NMR (100 MHz,
CDCl3), d (ppm): 85.67, 87.63, 105.17, 124.35, 124.58, 125.86, 126.54, 127.02,
127.99, 128.32, 128.80, 129.73, 133.54, 133.72, 134.15, 135.83, 138.42.
Synthesis of monobenzylethers 10b-c, e. To a solution of the
dioxolane 9b,c,e (1.82 mmol) in toluene (10 ml), under nitrogen, a solu-
tion of DIBALH (6.64 mmol) was slowly added at 08C. The reaction was
monitored by GC–MS analysis. The reaction was quenched with a few
drops of methanol, then the solution was diluted with diethyl ether,
washed with 10% aqueous NaOH, brine and dried over Na2SO4. After the
evaporation of the solvent, the residue was purified by chromatography
column (SiO2, petroleum ether/Et2O 3:1).
(1R,2R)-2-(Naphthalen-1-yl-methoxy)-1,2-diphenylethanol
(10b). Yield 82% (white solid); m.p. 5 70–728C; [a]20 5 241.8 (c
D
1.08, CHCl3); MS (EI): m/z 141 (M1 2 C14H13O2, 100), 107 (32), 79
(11); 1H NMR (400 MHz, CDCl3) d (ppm): 3.34 (bs, 1H), 4.35 (d, J 5 8.0
Hz, 1H), 4.68 (d, J 5 11.6 Hz, 1H), 4.90 (d, J 5 11.6 Hz, 1H), 6.92–6.94
(m, 2H), 7.04–7.08 (m, 5H), 7.16–7.20 (m, 3H), 7.33–7.37 (m, 2H), 7.41–
7.48 (m, 2H), 7.76 (dd, J1 5 6.8 Hz, J2 5 2.0 Hz, 1H), 7.80 (d, J 5 7.2 Hz,
1H), 7.96 (d, J 5 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3), d (ppm):
69.47, 78.72, 87.39, 123.92, 125.41, 126.08, 126.66, 127.12, 127.44, 127.84,
128.00, 128.16, 128.40, 128.90, 129.14, 132.00, 134.00, 137.76, 139.32.
(1R,2R)-2-(Naphthalen-2-yl-methoxy)-1,2-diphenylethanol (10c).
Yield 76% (white solid); m.p. 5 91–938C; [a]20 5 228.0 (c 1.03, CHCl3);
Synthesis of (4R,5R)-2-aryl-4,5-diphenyl-1,3-dioxolanes 9b-
c,e. A solution of arylaldehyde (2.81 mmol), (R,R)-8a or (R,R)-8b
(2.34 mmol) and traces of p-toluensulfonic acid in toluene (30 ml) was
heated at reflux under Dean-Stark conditions. The reaction was moni-
tored by GC–MS analysis. After complete conversion, the solvent was
removed at reduced pressure, and the residue was purified by column
chromatography (SiO2, CHCl3, or CHCl3/petroleum ether).
D
1H NMR (400 MHz, CDCl3) d (ppm): 3.56 (s, 1H), 4.41 (d, J 5 8.2 Hz, 1H),
4.49 (d, J 5 11.6 Hz, 1H), 4.70 (d, J 5 11.6 Hz, 1H), 4.77 (d, J 5 8.2 Hz,
1H), 7.00–7.30 (m, 4H), 7.40–7.50 (m, 5H), 7.73 (s, 1H), 7.8–7.9 (m, 7H);
13C NMR (100 MHz, CDCl3), d (ppm): 72.89, 77.65, 90.35, 125.43, 126.32,
127.51, 127.82, 128.65, 128.92, 131.65, 133.82, 135.25, 136.90, 138.43.
(1R,2R)-2-(Benzyloxy)-1,2-di(naphthalen-2-yl)ethanol (10e).
Yield 64% (yellow pale oil); [a]20 5 1103.6 (c 0.80, CHCl3); 1H NMR
(4R,5R)-2-(Naphthalen-1-yl)-4,5-diphenyl-1,3-dioxolane (9b). Yield
D
78% (white solid); m.p. 5 83–868C; [a]20 5 213.3 (c 1.01, CHCl3); MS
(400 MHz, CDCl3) d (ppm): 3.63 (bs, 1H), 4.30 (d, J 5 11.2 Hz, 1H), 4.47
(d, J 5 11.2 Hz, 1H), 4.55 (d, J 5 8.0 Hz, 1H), 4.95 (d, J 5 8.0 Hz, 1H),
7.00 (d, J 5 8.4 Hz, 1H), 7.09 (d, J 5 7.6 Hz, 2H), 7.16 (d, J 5 8.0 Hz,
2H), 7.22–7.37 (m, 7H), 7.48–7.64 (m, 6H), 7.71 (d, J 5 7.2 Hz, 1H); 13C
NMR (100 MHz, CDCl3), d (ppm): 71.15, 78.69, 87.03, 125.49, 125.55,
125.63, 126.02, 126.35, 126.60, 127.69, 127.79, 127.94, 128.19, 128.22,
128.28, 128.34, 128.48, 128.78, 129.29, 133.24, 133.27, 133.29, 133.52,
135.28, 136.96, 137.88.
D
(EI): m/z 246 (M1 2 PhCHO, 100), 217 (58), 167 (12), 155 (24), 139
1
(28), 127 (15); H NMR (400 MHz, CDCl3) d (ppm): 5.05 (d, J 5 8.0 Hz,
1H), 5.14 (d, J 5 8.0 Hz, 1H), 7.09 (s, 1H), 7.37–7.43 (m, 10H), 7.55–7.61
(m, 3H), 7.94 (d, J 5 8.0 Hz, 2H), 8.05 (d, 7.2 Hz,1H), 8.40 (d, J 5 8.4
Hz, 1H); 13C NMR (100 MHz, CDCl3), d (ppm): 85.41, 87.54, 103.19,
123.82, 124.39, 125.39, 126.02, 126.66, 126.73, 127.23, 128.51, 128.77,
128.83, 129.96, 131.29, 133.55, 134.08, 136.76, 138.43.
(4R,5R)-2-(Naphthalen-2-yl)-4,5-diphenyl-1,3-dioxolane (9c). Yield
Synthesis of (4R,5R)-4,5-diphenyl-30,40-dihydro-20H-spiro[[1,3]
dioxolane-2,10-naphthalene] (12). To
a solution of a-tetralone
66% (white solid); m.p. 5 82–858C; [a]20 5 21.4 (c 1.03, CHCl3); 1H
D
Chirality DOI 10.1002/chir

ASYMMETRIC ADDITION TO ALKYLIDENMALONATES
763
(0.45 ml, 3.42 mmol) in methanol (7.5 ml), trimethyl orthoformate (0.75
ml, 6.84 mmol) and traces of p-toluensulfonic acid were added. The red–
orange solution was stirred at room temperature for 6 h monitoring the
reaction by GC–MS analysis. Then the reaction mixture was diluted with
diethyl ether and treated with aqueous 1 M NaOH. The aqueous phase
was extracted with diethyl ether and the combined organic layers were
washed with brine, dried over Na2SO4, and concentrated at reduced
pressure to give 1,1-dimethoxy-1,2,3,4-tetrahydronaphthalene (0.60 g,
3.10 mmol, which was dissolved in chloroform (39 ml). To this solution,
2H), 7.1–7.5 (m, 20H), 7.69 (d, J 5 9.0 Hz, 1H), 7.90–8.00 (m, 3H); 13C
NMR (125 MHz, CDCl3), d (ppm): 70.98, 81.18, 85.42, 122.30,122.41,
124.93, 125.19, 126.16, 126.38, 127.30, 127.71, 127.80, 127.90, 128.04,
128.22, 128.34, 128.53, 129.72, 130.40, 131.72, 133.07, 137.48, 138.03,
138.31, 147.60.
(aR,R,R)-L2b. Yield (22%); m.p. 5 152–1558C; [a]20 5 2176.1 (c
D
1.01, CHCl3); 1H NMR (400 MHz, CDCl3), d (ppm): 4.63 (d, J 58.0 Hz,
1H), 4.94 (s, 2H), 5.44 (dd, J1 5 9.6 Hz, J2 5 8.0 Hz, 1H), 6.73 (d, J 5 8.8
Hz, 1H), 6.97 (t, J 5 7.2 Hz, 2H), 7.11 (d, J 5 10.0 Hz, 2H), 7.14–7.27 (m,
10H), 7.31–7.52 (m, 6H), 7.66–7.69 (m, 2H), 7.77–7.89 (m, 6H); 13C NMR
(125 MHz, CDCl3), d (ppm): 66.52, 89.45, 103.42, 122.71, 124.22, 125.86,
126.11, 126.36, 127.28, 127.90, 127.97, 128.20, 128.34, 128.45, 128.63,
131.35, 131.61, 133.76, 137.49, 139.61, 167.14, 167.82.
˚
(R,R)-8a (0.64 g, 3.00 mmol), activated molecular sieves (4 A), traces of
p-toluensulfonic acid were added, and the mixture was stirred at room
temperature for 20 h. The reaction was monitored by GC–MS analysis.
Filtration and evaporation of solvent at reduced pressure gave the crude
product, which was purified by chromatography column (SiO2, petro-
leum ether/dichloromethane 6:4) to provide 12 (0.69 g, 67%) as white
solid.
(aR,R,R)-L2c. Yield (35%); m.p. 5 173–1768C; [a]20 5 2184.5 (c
D
1.01, CHCl3); 1H NMR (400 MHz, CDCl3), d (ppm): 4.46 (d, J 5 8.0 Hz,
M.p. 5 109–1118C; [a]20 5 169.9 (c 1.02, CHCl3); MS (EI): m/z 236
D
(M1 2 PhCHO, 100), 218 (13), 208 (12), 180 (29), 167 (16), 129 (24),
1H), 4.55 (d, J 5 12.0 Hz, 1H), 4.63 (d, J 5 12.0 Hz, 1H), 5.38 (dd, J1
5
1
9.2 Hz, J2 5 8.4 Hz, 1H), 6.74 (d, J 5 8.8 Hz, 1H), 6.89 (d, J 5 7.2 Hz,
2H), 6.97–7.01 (m, 2H), 7.07–7.21 (m, 10 H), 7.29–7.46 (m, 6H), 7.64–
7.83 (m, 8H); 13C NMR (100 MHz, CDCl3), d (ppm): 71.20, 86.05, 107.91,
122.21, 122.80, 123.26, 125.16, 125.55, 126.15, 126.23, 126.33, 127.27,
127.89, 127.99, 128.30, 128.40, 128.49, 129.29, 130.27, 131.39, 131.68,
132.82, 133.02, 133.16, 133.57, 136.11, 137.48, 167.75.
118 (21), 91 (14); H NMR (400 MHz, CDCl3), d (ppm): 2.02 (q, J 5 6.0
Hz, 2H), 2.25 (t, J 5 6.0 Hz, 2H), 2.79 (t, J 5 6.4 Hz, 2H), 4.85 (d, J 5 8.4
Hz, 1H), 5.01 (d, J 5 8.4 Hz, 1H), 7.06 (d, J 5 7.2 Hz, 1H), 7.14–7.25 (m,
12H), 7.77 (d, J 5 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3), d (ppm):
21.10, 29.35, 35.68, 85.43, 86.92, 108.20, 126.61, 126.72, 126.82, 127.26,
127.28, 128.38, 128.65, 128.78, 128.91, 136.38, 137.84, 138.14, 138.80.
(aR,R,R)-L2d. Yield (14%); m.p. 5 108–1108C; [a]20 5 226.3 (c
D
Synthesis of (1R,2R)-1,2-diphenyl-2-(1,2,3,4-tetrahydronaph-
thalen-1-yloxy)ethanol (13). To a solution of 12 (0.63 g, 1.85 mmol)
in dichloromethane (10 ml), a solution of DIBALH (7.4 ml, 6 eq., 11.10
mmol) was slowly added at 08C. The reaction was monitored by GC–MS
analysis. The reaction was quenched with a few drops of methanol, then
diluted with diethyl ether, washed with 10% aqueous NaOH, brine, and
dried over Na2SO4. The evaporation of solvent gave the product 13
(0.58 g, 91%) as colorless oil.
1.00, CHCl3); 1H NMR (400 MHz, CDCl3), d (ppm): 4.52 (d, J 5 10.0 Hz,
1H), 4.57 (d, J 5 10.0 Hz, 1H), 4.75 (d, J 5 8.0 Hz, 1H), 5.44 (t, J 5 8.8
Hz, 1H), 6.64 (d, J 5 7.2 Hz, 1H), 6.70 (d, J 5 7.6 Hz, 1H), 6.83 (d, J 5
8.8 Hz, 1H), 6.95–7.65 (m, 20H), 7.73 (d, J 5 8.4 Hz, 1H), 7.80–7.97 (m,
6H), 8.04 (d, J 5 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3), d (ppm):
75.83, 91.47,73.94, 119.00, 124.41, 126.63, 126.91, 127.68, 127.89, 127.99,
128.00, 128.61, 128.89, 129.20, 129.48, 130.77, 133.87, 137.41, 141.87,
153.00.
[a]20 5 279.8 (c 1.17, CHCl3); MS (EI): m/z 131 (M1 2 C14H13O2,
D
1
100), 213 (15), 107 (78), 91 (19), 79 (16); H NMR (400 MHz, CDCl3), d
(aR,R,R)-L2e. Yield (32%); m.p. 5 126–1298C; [a]20 5 2153.2 (c
D
(ppm): 1.18–1.57 (m, 2H), 1.76–1.82 (m, 1H), 1.90–1.96 (m, 1H), 2.56–
2.64 (m, 1H), 2.77 (dt, J1 5 16.4 Hz, J2 5 5.2 Hz, 1H), 3.35 (s, 1H), 4.39–
4.42 (m, 2H), 4.57 (d, J 5 8.0 Hz, 1H), 6.90–6.93 (m, 2H), 7.01–7.19 (m,
12H); 13C NMR (100 MHz, CDCl3), d (ppm): 18.26, 28.89, 29.78, 75.41,
79.12, 86.94, 125.90, 127.50, 127.80, 128.10, 128.20, 128.30, 129.70.
136.30, 138.10, 139.30, 139.50.
1.01, CHCl3); 1H NMR (400 MHz, CDCl3), d (ppm): 1.46–1.57 (m, 2H),
1.69–1.74 (m, 1H), 1.88–1.93 (m, 1H), 2.58 (dt, J1 5 16.8 Hz, J2 5 6.8 Hz,
1H), 2.76 (dt, J1 5 16.8 Hz, J2 5 6.0 Hz, 1H), 4.49 (t, J 5 4.6 Hz, 1H), 4.58
(d, J 5 7.6 Hz, 1H), 5.27 (dd, J1 5 10.4 Hz, J2 5 8.0 Hz, 1H), 6.39 (d, J 5
8.8 Hz, 1H), 6.87 (d, J 5 7.2 Hz, 2H), 6.97–7.37 (m, 18H), 7.43 (d, J 5 8.8
Hz, 1H), 7.53 (d, J 5 8.8 Hz, 1H), 7,77 (d, J 5 8.0 Hz, 1H), 7.83 (d, J 5 8.4
Hz, 1H), 7.88 (d, J 5 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3), d (ppm):
18.51, 28.91, 29.59, 76.00, 84.57, 87.91, 115.71, 122.06, 122.59, 123.05,
124.90, 125.18, 125.56, 126.10, 126.37, 127.22, 127.93, 128.11, 128.30,
129.20, 129.45, 130.41, 131.31, 132.71, 134.13, 136.70, 138.00, 138.19,
139.32, 148.23; 31P NMR (162 MHz, CDCl3), d (ppm):152.22.
Synthesis of phosphites (aR,R,R)-L2a-e, (aS,R,R)-L3a, (aS,R,R)-
L3e and (aR,R,R)-L4. A solution of monoprotected diarylethane-1,2-
diols 10a–e or 13 (1.96 mmol) in toluene (6 ml) was slowly added to a
cooled solution (–608C) of freshly distilled phosphorus trichloride (171
ll, 1.96 mmol) and triethylamine (1.4 ml, 10.24 mmol) in toluene (4 ml).
The mixture was stirred at 2608C for 2 h. Then DMAP (261 mg, 2.14
mmol) was added to the solution, and a solution of (R) or (S)-BINOL
(561 mg, 1.96 mmol) was added dropwise in toluene (16 ml). The solu-
tion was stirred at 2608C for 2 h. The reaction was monitored by TLC.
The reaction mixture was filtered and concentrated at reduced pressure.
The purification of the crude product, by chromatography column (SiO2,
dichloromethane/petroleum ether 2:1), gave the phosphite as white
solid.
(aS,R,R)-L3e. Yield (52%); m.p. 5 137–1398C; [a]20 5 1205.7 (c
D
1.00, CHCl3); 1H NMR (400 MHz, CDCl3), d (ppm): 1.43–1.55 (m, 2H),
1.90–1.92 (m, 1H), 2.12–2.14 (m, 1H), 2.54–2.65 (m, 1H), 2.72–2.76 (m,
1H), 4.30–4.33 (m, 1H), 4.66 (d, J 5 6.8 Hz, 1H), 5.23 (dd, J1 5 8.8 Hz, J2
5 6.8 Hz, 1H), 6.16 (d, J 5 8.4 Hz, 1H), 6.65 (d, J 5 7.2 Hz, 2H), 6.92–
7.34 (m, 18H), 7.46 (d, J 5 8.8 Hz, 1H), 7.76–7.88 (m, 4H); 13C NMR
(100 MHz, CDCl3), d (ppm): 17.99, 29.74, 35.17, 73.39, 86.97, 96.39,
124.80, 125.21, 125.51, 125.97, 126.26, 127.35, 127.64, 127.69, 127.90,
128.15, 128.37, 128.42, 129.45, 129.91, 130.26, 132.58, 133.04, 138.50,
138.72, 139.31, 139.91, 150.42, 157.40; 31P NMR (162 MHz, CDCl3), d
(ppm):144.33.
(aR,R,R)-L2a. Yield (55%); m.p. 5 107–1098C; [a]20 5 2246.0 (c
D
0.55, CHCl3); 1H NMR (500 MHz, CDCl3), d (ppm): 4.48 (d, J 5 11.7 Hz,
1H), 4.49 (d, J 5 8.1 Hz), 4.53 (d, J 5 11.7 Hz, 1H), 5.42 (dd, J1 5 8.7
Hz, J2 5 8.1 Hz, 1H), 6.81 (d, J 5 8.7 Hz, 1H), 6.93 (d, J 5 7.2 Hz, 2H),
7.06 (d, J 5 6.4 Hz, 2H), 7.1–7.4 (m, 18 H), 7.72 (d, J 5 9.0 Hz, 1H), 7.8–
7.9 (m, 3H); 13C NMR (125 MHz, CDCl3), d (ppm): 70.97, 81.46, 85.91,
121.95, 122.57, 124.68, 124.91, 125.69, 126.10, 127.03, 127.09,127.39,
127.53, 127.67, 127.72, 127.95, 128.08, 129.24, 128.28, 129.20, 130.06,
131.19, 131.49, 132.63, 132.86, 137.30, 137.55, 138.46, 147.70, 148.23.
(aR,R,R)-L4. Yield (50%); m.p. 5 165–1688C; [a]20 5 293.3 (c
D
1
1.00, CHCl3); H NMR (400 MHz, CDCl3), d (ppm): 4.43 (d, J 511.2 Hz,
1H), 4.48 (d, J 512.0 Hz, 1H), 4.67 (d, J 57.6 Hz, 1H), 5.64 (dd, J1 5 9.2
Hz, J2 5 8.0 Hz, 1H), 6.66 (d, J 58.8 Hz, 1H), 6.88 (d, J 57.2 Hz, 1H),
7.05–7.41 (m, 20H), 7.47–7.59 (m, 5H), 7.69 (d, J 56.8 Hz, 2H), 7.80–7.83
(m, 2H); 13C NMR (100 MHz, CDCl3), d (ppm): 71.25, 81.20, 86.09,
122.12, 122.84, 123.31, 125.17, 125.69, 125.83, 126.32, 127.28, 127.48,
127.86, 128.29, 128.51, 130.32, 130.80, 131.43, 131.71, 132.86, 133.10,
133.24, 133.27, 133.48, 134.94, 135.31, 138.51, 145.61, 148.07, 148.34,
156.31.
(aS,R,R)-L3a. Yield (20%); m.p. 5 97–1008C; [a]20 5 1221.0 (c
D
0.53, CHCl3); 1H NMR (500 MHz, CDCl3), d (ppm): 4.50 (d, J 5 11.7 Hz,
1H), 4.56 (d, J 5 11.7 Hz, 1H), 4.64 (d, J 5 7.5 Hz, 1H), 5.43 (dd, J1
5
7.8 Hz, J2 5 7.5 Hz, 1H), 6.90 (d, J 5 7.5 Hz, 1H), 7.06 (d, J 5 8.0 Hz,
Chirality DOI 10.1002/chir

764
SUPERCHI ET AL.
3), 160 (49), 145 (8), 131 (33), 117 (30), 104 (85), 92 (53), 91 (100); 1H
Synthesis of racemic 3-methyl-5-phenylpentanoate (7). To a
NMR (400 MHz, CDCl3) d(ppm): 0.99 (d, J 5 6.5 Hz, 3H), 1.45–1.52 (m,
2H), 1.64–1.71 (m, 3H), 2.60–2.76 (m, 2H), 3.43 (d, J 5 6.5 Hz, 1H),
3.68–3.76 (m, 2H), 7.18–7.21 (m, 3H), 7.28–7.31 (m, 2H); 13C NMR (100
MHz, CDCl3) d(ppm): 19.79, 29.50, 33.62, 39.26, 40.05, 61.33, 125.89,
128.57, 129.28, 143.06.
mixture of MeMgBr (800 ll, 2.30 mmol) and CuCl (80 mg, 0.78 mmol)
in Et2O (2.3 ml), a solution of diethyl 3-phenylpropylidenemalonate (5)
(160 mg, 0.58 mmol) in Et2O (2.3 ml) was added, and the mixture was
stirred at room temperature for 2 h. The reaction was monitored by GC–
MS analysis. The reaction was quenched with 10% aqueous HCl, and the
solution extracted with Et2O. The organic phases were washed with
brine, dried over anhydrous Na2SO4. The evaporation of solvent at
reduced pressure gave diethyl 2-(4-phenylbutan-2-yl)malonate (6) (91
mg, 0.31 mmol) which was dissolved in DMF (1.1 ml). To this solution,
H2O (11 ll, 0.62 mmol) and LiCl (53 mg, 1.24 mmol) were added, and
the reaction mixture was heated to reflux for 20 h. After cooling at room
temperature, water was added and the mixture was extracted with ethyl
acetate. The organic layer was washed with brine and dried over
Na2SO4. The evaporation of solvent at reduced pressure gave the crude
product, which was purified by chromatography column (SiO2, petro-
leum ether/CH2Cl2 8:2) to provide ethyl 3-methyl-5-phenylpentanoate
(7) (34 mg, 50%) as pale yellow oil. The two enantiomers were separated
by HPLC on Chiralcel OJ-H column, 210 nm, 0.5 ml/min, hexane/2-pro-
panol 90/10. MS (EI): m/z 220 (M1, 3), 174 (79), 131 (32), 104 (24), 91
(100); 1H NMR (400 MHz, CDCl3) d(ppm): 0.93 (d, J 5 6.4 Hz, 3H), 1.17
(t, J 5 7.2 Hz, 3H), 1.40–1.50 (m, 1H), 1.53–1.62 (m, 1H), 1.91–2.00 (m,
1H), 2.05–2.12 (m, 1H), 2.28 (dd, J1 5 15.6 Hz, J2 5 6.0 Hz, 1H), 2.52–
2.62 (m, 2H), 4.04 (q, J 5 7.2 Hz, 2H), 7.10–7.21 (m, 5H); 13C NMR (100
MHz, CDCl3) d(ppm): 14.48, 19.88, 29.94, 33.57, 38.78, 42.05, 49.91,
60.41, 124.40, 128.59, 131.60, 136.80, 168.38.
Synthesis of 3-methyl-5-phenylpentanal (Citralis). To a solution
of pyridinium chlorochromate (224 mg, 1.04 mmol) in CH2Cl2 (1.8 ml),
3-methyl-5-phenylpentan-1-ol (93 mg, 0.52 mmol) in CH2Cl2 (0.2 ml) was
added, and the solution was stirred at room temperature for 1 h. The
reaction was monitored by GC–MS. After removal of the solvent, the res-
idue was diluted with Et2O and filtered through a short plug of silica gel
to afford (R)-Citralis (65 mg, 71%), which was utilized in the next step
without purification. [a]20 5 117.4 (c 1.0, CH2Cl2) (74% ee); MS (EI):
D
m/z 176 (M1, 31), 158 (13), 143 (36), 131 (22), 117 (42), 105 (20), 92
1
(36), 91 (100), 71 (24); H NMR (400 MHz, CDCl3) d(ppm): 1.03 (d, J 5
7.0 Hz, 3H), 1.64–1.70 (m, 2H), 2.09–2.13 (m, 1H), 2.28 (ddd, J1 5 16.0
Hz, J2 5 7.5 Hz, J3 52.5 Hz, 1H), 2.44 (dd, J1 5 16.0 Hz, J2 5 4.0 Hz,
1H), 2.57–2.71 (m, 2H), 7.17–7.20 (m, 2H), 7.26–7.29 (m, 3H), 9.75 (s,
1H); 13C NMR (100 MHz, CDCl3) d(ppm): 19.79, 27.80, 33.16, 38.58,
50.90, 125.80, 128.29, 128.40, 142.03, 202.68.
Synthesis of 3-methyl-5-phenylpentanenitrile (Nitrile Citralis).
To a solution of NH2OHꢁHCl (34 mg, 0.48 mmol), NaI (28 mg, 0.18
mmol) in MeCN (1.5 ml) was added a solution of 3-methyl-5-phenylpen-
tanal (65 mg, 0.37 mmol) in MeCN (2 ml), and the reaction mixture was
heated at reflux for 1 h. The reaction was monitored by GC–MS. The
red mixture was cooled to room temperature, quenched with 5% aqueous
Na2S2O3 and stirred until complete disappearance of the red color. The
solution was diluted with CH2Cl2, the organic layer was washed with
brine and dried over Na2SO4. The evaporation of solvent at reduced
pressure gave the (R)-Nitrile Citralis (53 mg, 83%). [a]20D 5 21.7 (c 3.0,
CH2Cl2) (74% ee); MS (EI): m/z 173 (M1, 20), 158 (43), 92 (29), 91
(100); 1H NMR (400 MHz, CDCl3) d(ppm): 1.06 (d, J 5 6.8 Hz, 3H),
1.59–1.69 (m, 2H), 1.80–1.90 (m, 1H), 2.51–2.64 (m, 4H), 7.06–7.25 (m,
5H); 13C NMR (100 MHz, CDCl3) d(ppm): 19.29, 24.50, 29.87, 33.00,
37.48, 118.68, 126.00, 128.16, 128.50, 141.28.
General Procedure
Enantioselective Addition of Me2Zn to diethyl 3-phenylpropyli-
denemalonate (5). A solution of flamed dried Cu(OTf)2 (8.1 mg,
0.022 mmol, 4 mol %) and phosphoramidite or phosphite ligand (0.045
mmol, 8 mol %) in freshly distilled toluene (4 ml) was stirred at room
temperature for 1 h. After cooling to 2408C, diethyl 2-(3-phenylpropyli-
dene)malonate (5) (155 mg, 0.56 mmol) and Me2Zn (0.7 ml, 2 eq., 1.12
mmol) were slowly added. The reaction was monitored by GC–MS anal-
ysis. After complete conversion, the mixture was poured into a solution
of saturated NH4Cl and ethyl acetate. The separated organic layer was
washed with brine and dried over Na2SO4. The evaporation of solvent at
reduced pressure gave the diethyl 2-(4-phenylbutan-2-yl)malonate (6)
(159 mg, 97%). This compound was deethoxycarbonylated to 7 accord-
ing to the procedure reported above for the racemic mixture. Enantio-
meric excesses were determined by HPLC, in the same conditions
reported above.
RESULTS AND DISCUSSION
At first, phosphoramidite (S)-L115,16 and phosphites
(aR,R,R)-L2a and (aS,R,R)-L3a17 (Chart 1) which proved to
efficiently catalyze the asymmetric addition of dimethylzinc
to macrocyclic enones, were tested as ligands in the copper-
catalyzed asymmetric addition of dimethylzinc to diethyl 3-
phenylpropylidenmalonate (5) (Table 1), screening various
temperatures to find the best experimental conditions for the
two ligands. Performing the reaction at 2608C phosphorami-
dite (S)-L1 provided very poor stereoselection (10% ee) after
30 h (Entry 1), while increasing the temperature better
yields and enantiomeric excesses (Entries 2–4) were
obtained, arriving up to 66% ee at 08C (Entry 4). On the con-
trary, (aR,R,R)-L2a provided the highest yield and e.e (72%)
at 2408C (Entry 6). The diastereoisomeric phosphite
Synthesis of 3-methyl-5-phenylpentan-1-ol (Phenoxanol). Under
nitrogen atmosphere, to a solution of (R)-ethyl-3-methyl-5-phenylpenta-
noate (7) (74% ee) (124 mg, 0.56 mmol) in Et2O (2.8 ml), at 08C,
DIBALH (1.12 ml, 3 eq., 1.68 mmol) was slowly added. The reaction mix-
ture was stirred, at the same temperature, for 16 h. The solution was
diluted with Et2O and quenched with brine. Then HCl 4 M was added
dropwise under stirring until two clear and separated phases were
formed. The aqueous layer was extracted with Et2O, and the combined
organic phases were washed with brine and dried over Na2SO4. The
evaporation of solvent at reduced pressure gave (R)-Phenoxanol (93 mg,
93%). [a]20 5 111.0 (c 3.00, CH2Cl2) (74% ee); MS (EI): m/z 178 (M1,
D
Chart 1. Structures of ligands L1, L2a, L3a.
Chirality DOI 10.1002/chir

ASYMMETRIC ADDITION TO ALKYLIDENMALONATES
765
TABLE 1. Asymmetric addition of Me2Zn to diethyl 3-phenyl-
propylidenmalonate (5) with L1, L2a, and L3a
lectivity. To this end, several new phosphites derived from
BINOL but displaying different alcoholic moieties were syn-
thesized (Chart 2). A summary of the synthetic steps for
their preparation is reported in the Scheme 2.
We first synthesized and tested ligands (aR,R,R)-L2b-d,
which share a different monoprotection of the alcohol part
deriving from the diol.18 (R,R)-1,2-diphenylethane-1,2-diol
(8a)20 and (R,R)-1,2-di(2-naphthyl)ethane-1,2-diol (8b)21
were obtained by asymmetric dihydroxylation of the corre-
sponding alkenes. Acetals 9a–e were prepared in 80–90%
yield by reacting (R,R)-8a,b with a suitable arylaldehyde and
a catalytic amount of p-TsOH, in refluxing benzene under
water removal using a Dean-Stark condenser.18,19 The mono-
benzylethers 10a–e were obtained in 70–90% yield by reduc-
tion of the acetals 9a–e with a threefold excess of DIBALH
in dry toluene at 08C.18,19 Monoprotected diols 10a–e were
then transformed in the corresponding dichlorophosphites
11a–e by treatment with phosphorus trichloride and triethyl-
amine in toluene. Further treatment of 11a–e with (R) or
(S)-BINOL at 2608C in toluene in the presence of DMAP
provided the desired phosphites L2a-d and L4. These phos-
phites were then screened using the experimental conditions
optimized for (aR,R,R)-L2a (Table 2) obtaining enantioselec-
tivity (ee 62–74%) comparable with that achieved with this
ligand (Table 2, Entries 1–3).
We thought then that a reduction of the conformational
freedom of the benzylic protecting group of the alcoholic
function could have a positive effect on the efficiency of the
ligand. Therefore, we projected a phosphite in which the ben-
zylic carbon linked to the oxygen of the diol was inserted in
a cycle, then limiting its conformational flexibility. Therefore,
starting from tetralone acetal 12 was prepared with diol
(R,R)-8a (Scheme 3). The acetal was then opened into the
corresponding monoprotected diol 13 by treatment with
DIBALH. From both 1H NMR and 13C NMR analyses of
crude, a single set of signals allied to a single diaster-
eoisomer of 13 was detected (see Experimental Section), in
agreement with results previously reported by Sharpless.20
Entries
Ligand
T (8C)
Yield (%)a
ee (%)b A.C.c
1d
2
3
4
5
6
7
8
9
(S)-L1
(S)-L1
(S)-L1
260
240
220
0
260
240
220
0
79
96
95
87
70
93
91
61
54
10 (S)
50 (S)
44 (S)
66 (S)
64 (R)
72 (R)
48 (R)
48 (R)
18 (S)
(S)-L1
(aR,R,R)-L2a
(aR,R,R)-L2a
(aR,R,R)-L2a
(aR,R,R)-L2a
(aS,R,R)-L3a
240
aIsolated yield.
bDetermined by chiral HPLC analysis of the corresponding monoester 7.
cDetermined from sign of optical rotation of the corresponding monoester 7
(see Ref. 11).
dComplete conversion after 30 h.
(aS,R,R)-L3a, in which the binaphthyl moiety have opposite
configuration, provided (Entry 9) a reversed enantioselectiv-
ity and significantly lower ee (18%) in respect to (aR,R,R)-
L2a. We can then deduce that in this reaction, although the
effect of the binaphthyl backbone is predominant in deter-
mining the direction of the asymmetric induction, also the
fragment derived from monoprotected diphenylethane-1,2-
diol plays an important role in the efficiency of phosphites as
chiral ligands. This is clear from the difference of ees values
achieved with the two diastereoisomer ligands.
Taking into account the aforementioned considerations as
well as the fact that, in this reaction, phosphite (aR,R,R)-L2a
provided the best results, we decided to modify the structure
of this easily tunable ligand to try to improve the enantiose-
Chart 2. Structures of new phosphites.
Chirality DOI 10.1002/chir

766
SUPERCHI ET AL.
Scheme 2. Reagent and conditions: (a) ArCHO, p-TsOH, toluene, Dean-Stark; (b) DIBAL, toluene, 08C; (c) PCl3, Et3N, toluene, 2608C; (d) DMAP, (R) or (S)-
BINOL, toluene, 2608C.
TABLE 2. Asymmetric addition of Me2Zn to diethylpropyliden-
malonate (6) with L2b-e, L3e, and L4
the ees obtained with the two matched and mismatched
pairs, (aR,R,R)-L2a versus (aS,R,R)-L3a and (aR,R,R)-L2e
versus (aS,R,R)-L3e (Table 1 Entries 6, 9 and Table 2
Entries 4, 5). Then we prepared phosphite (aR,R,R)-L4 from
1,2-di(2-naphthyl)-1,2-ethane-1,2-diol (8b),21 following the
same procedure described above for analogous phosphites
(Scheme 2). Also this ligand gave results comparable with
that obtained with the other phosphites, giving the product
in very high isolated yield and 68% ee.
Entries
Ligand
Yield (%)a
ee (%)b A.C.c
1
2
3
4
5
6
(aR,R,R)-L2b
(aR,R,R)-L2c
(aR,R,R)-L2d
(aR,R,R)-L2e
(aS,R,R)-L3e
(aR,R,R)-L4
91
41
66
60
97
96
62 (R)
70 (R)
74 (R)
50 (R)
20 (S)
68 (R)
CONCLUSIONS
With this investigation, we have shown that the changes of
steric hindrance introduced in the alcoholic part of phoshite
(aR,R,R)-L2a generally do not improve the efficiency of the
ligand in the copper-catalyzed asymmetric addition of dime-
thylzinc to 3-phenylpropylidenemalonate (6). In fact, only
(aR,R,R)-L2d, in which the benzylic group of (aR,R,R)-L2a
has been replaced by a biphenylmethyl moiety, provided a
slightly better enantioselectivity. Although this ligand
appears competitive in this reaction with respect to other
ligands reported in the literature,11 giving rise to the addition
product with a 74% ee and a very good yield (93%), we
believe that further structural changes on this very tunable
ligand could have positive effects on its efficiency as chiral
inducer.
Moreover, a new simple route to floral fragrances Phenox-
anol, Nitrile, and Nitrile Citralis, based on this reaction as
asymmetric step, has been also disclosed. This synthetic
strategy could represent a new convenient enantioselective
access not only to the above cited fragrances but also to a
range of structurally diverse 3-alkyl substituted esters, alco-
hols, aldehydes, and nitriles in optically active form.
aIsolated yield.
bDetermined by chiral HPLC analysis of the corresponding monoester 7.
cDetermined from sign of optical rotation of the corresponding monoester 7
(see Ref. 11).
The presence of only one diastereoisomer of 13 was also
confirmed by GC–MS analysis. At present, we were not, how-
ever, able to determine the absolute configuration of the new
benzylic stereogenic center. From alcohol 13 phosphites
(aR,R,R)-L2e and (aS,R,R)-L3e were prepared by reaction
with (R)- or (S)-BINOL, respectively (Scheme 2). 31P NMR
analysis of both phosphites showed the presence of a single
phosphorus signal, confirming the diastereoisomeric purity
of 13. These phosphites were then tested in the asymmetric
addition (Table 2, Entries 4 and 5). Unfortunately, the
change of the ligand structure and also the introduction of a
new chiral center gave negative effects on the efficiency of
the ligand reducing the contribution to the stereoselection of
the alcoholic part of the ligand. This appears clear comparing
˚
Scheme 3. Reagent and conditions: (a) CH(OCH3)3, p-TsOH, methanol, r.t.; (b) (R,R)-1,2-diphenylethane-1,2-diol, p-TsOH, molecular sieves (4A), CHCl3, r.t.;
(c) DIBAL, CH2Cl2, 08C; (d) PCl3, Et3N, toluene, 2608C; (e) DMAP, (R) or (S)-BINOL, toluene, 2608C.
Chirality DOI 10.1002/chir

ASYMMETRIC ADDITION TO ALKYLIDENMALONATES
767
12. Krapcho AP. Synthetic application of dealkoxycarbonylation of malonate
esters, b-keto esters, a-cyano esters and related compounds in dipolar
aprotic media-Part I. Synthesis 1982;805–822.
LITERATURE CITED
1. Alexakis A, B¨ackvall JE, Krause N, Pa`mies O, Die´guez M. Enantioselec-
tive copper-catalysed conjugate addition and allylic substitution reactions.
Chem Rev 2008;108:2796–2823.
13. Ciappa A, Bovo S, Bertolini M, Scrivanti A, Matteoli U. Homogeneous asym-
metric catalysis in fragrance chemistry. Chem Biodiv 2008;5:1058–1069.
2. Alexakis A, Benhaim C. Enantioselective copper-catalysed conjugate
addition. Eur J Org Chem 2002;3221–3236.
14. Matteoli U, Ciappa A, Bovo S, Bertoldini M, Scrivanti A. Asymmetric cata-
ysis in fragrance chemistry: a new synthetic approach to enantiopure
Phenoxanol1, Citralis1, and Citralis Nitrile1, Tetrahedron:Asymmetry
2007;18:797–802.
3. Krause N, Hoffmann-Ro¨der A. Recent advances in catalytic enantioselec-
tive Michael additions. Synthesis 2001;171–196.
4. Feringa ,BL. Phosphoramidites: marvellous ligands in catalytic asymmet-
ric conjugate addition. Acc Chem Res 2000;33:346–353.
15. Scafato P, Cunsolo G, Labano S, Rosini C. Asymmetric activation of tropos
catalysts in the stereoselective catalytic conjugate additions of R2Zn to a,b-
enones: an efficient synthesis of (-)-muscone. Tetrahedron 2004;60:8801.
5. Desrosiers J-N, Bechara WS, Charette AB. Catalytic enantioselective
addition of diorganozinc reagents to vinyl sulfones. Org Lett 2008;
10:2315–2318.
16. Scafato P, Larocca A, Rosini C. An alternative stereoselective synthesis of
the macrocylic fragrances (R)-12-methyltridecanolide and (S)-muscolide
by means of an asymmetric catalytic conjugate addition/Baeyer-Villiger
oxidation. Tetrahedron:Asymmetry 2006;17:2511–2515.
´
6. Bos PH, Macia´ B, Ferna´ndez-Iba´n˜ez MA , Minnaard AJ, Feringa BL. Cat-
alytic asymmetric conjugate addition of dialkylzinc reagents to a,b-unsat-
urated sulfones. Org Biomol Chem 2010;8:47–49.
17. Scafato P, Labano S, Cunsolo G, Rosini C. Catalytic enantioselective con-
iugate addition of dialkyl zinc reagents to a,b-unsaturated ketones medi-
ated by new phosphite ligands containing binaphtalene/1,2-diphenyl-
ethane moieties. Tetrahedron:Asymmetry 2003;14:3873–3877.
7. Palais L, Babel L, Quintard A, Belot S, Alexakis A. Copper-catalyzed
enantioselective 1,4-addition to a,b-unsaturated aldehydes. Org Lett
2010;12:1988–1991.
8. Harutyunyan S, den Hartog T, Geurts K, Minnaard AJ, Feringa BL. Cata-
lytic asymmetric conjugate addition and allylic alkylation with Grignard
reagents. Chem Rev 2008;108:2824–2852.
18. Superchi S, Contursi M, Rosini C. Monobenzylether of (R,R)-1,2-diphe-
nylethane-1,2-diol as chiral auxiliary in the diastereoselective reduction of
a-ketoesters. Tetrahedron 1998;54:11247–11254.
9. Wang S-Y, Loh T-P. Highly efficient enantioselective Cu(I)-Tolyl-BINAP-
catalyzed asymmetric conjugate addition of Grignard reagents to a,b-un-
saturated esters. Chem Commun 2010;46:8694–8703.
19. Scafato P, Leo L, Superchi S, Rosini C. Monobenzylethers of (R,R)-1,2-
diphenylethane-1,2-diol as a possible alternative to cyclohexyl-based chi-
ral auxiliaries in the stereoselective reduction of a-ketoesters. Tetrahe-
dron 2002;58:153–159.
10. Knochel P, Singer RD. Preparation and reactions of polyfunctional orga-
nozinc reagents in organic synthesis. Chem Rev 1993;93:2117–2188.
20. Kolb HC, VanNieuwenhze MS, Sharpless KB. Catalytic asymmetric dihy-
droxylation. Chem Rev 1994;94:2483–2547.
11. Schuppan J, Minnaard AJ, Feringa BL.
A catalytic and iterative
route to b-substituted esters via highly enantioselective conjugate addi-
tion of dimethylzinc to unsaturated malonates. Chem Commun 2004;
792–793.
21. Rosini C, Scamuzzi S, Uccello-Barretta G, Salvadori P. Synthesis and ster-
eochemical characterization of some optically active 1,2-dinaphthyl-
ethane-1,2-diols. J Org Chem 1994;59:7395–7400.
Chirality DOI 10.1002/chir