Stereoselective conjugate addition of diethylzinc to enones and nitroalkenes

Article abstract of DOI:10.1016/S0957-4166(02)00838-8

Bidirectionally directed conjugate addition of diethylzinc to enones and nitroalkene was achieved with good enantioselectivity.

Full text of DOI:10.1016/S0957-4166(02)00838-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 305–315
Stereoselective conjugate addition of diethylzinc to enones and
nitroalkenes
Jahyo Kang,* Jae Hoon Lee and Dae Sung Lim
Department of Chemistry, Sogang University, Seoul 121-742, South Korea
Received 22 October 2002; revised 6 December 2002; accepted 9 December 2002
Abstract—Bidirectionally directed conjugate addition of diethylzinc to enones and nitroalkene was achieved with good enantiose-
lectivity. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
conjugate addition of dialkylzinc catalyzed by Cu-chiral
phosphorus amidite complexes,8 and Alexakis et al.
reported on the conjugate addition of diethylzinc to
several nitroolefins catalyzed with trivalent phosphorus
ligands including phosphorus amidite.9 Recently, Hov-
eyda et al. reported on the highly enantioselective con-
jugate addition of diethylzinc to acyclic enones.10
Design of catalytic asymmetric reactions is usually cen-
tered around the development of optically active cata-
lysts that will bind substrates unambiguously before
reaction, direct the reactant to the reaction center, and
finally exchange the coordinated guests from the
product molecule for an unreacted substrate, thus
affording a catalytic cycle. However, it would be prefer-
able to have the ability to deliver a reactant that is
already bound to a certain part of the catalyst, espe-
cially to the coordinated substrate. In this way the
direction of attack can be closely controlled. This con-
cept is not new—in the 1980s Hayashi et al. utilized
hydrogen bonding of stabilized carbanions with the
hydroxyl group of the ligand for enantioselective Pd-
catalyzed allylation.1 CBS reduction,2 amino alcohol
(or thiol)-catalyzed addition of organozinc reagents to
aldehydes,3 and Shibasaki’s cyanosilylation4 and Reis-
sert reactions5 are noteworthy among other examples of
this type of stereocontrol.
Previously, we examined thianickelolidine ligands for
conjugate addition of dialkylzinc reagents to enones,
where a sulfur centre was used as an anchor for
diethylzinc. The enantioselectivity was found to be only
moderate (62–74%) in the case of chalcone (Fig. 1).11
The
enantioselective
conjugate
addition
of
organometallic reagents to a,b-unsaturated substrates,
such as enone6 and nitroolefin,7 is of considerable syn-
thetic interest. In many cases, phosphorus-containing
ligands such as phosphorus amidite, oxazoline-phos-
phite and phosphite ligands showed excellent enantiose-
lectivities in the copper-catalyzed Michael addition of
organozinc or organomagnesium reagents to enones
and other a,b-unsaturated carbonyl compounds.
Feringa et al. reported on the highly enantioselective
Figure 1.
2. Results and discussion
2.1. Synthesis of ligands
Herein, we report an extension of this concept to
BINOL derivatives, which simultaneously provide a
Lewis acidic site (for activation of enone) and the
anchoring site(s) for organo copper species formed
* Corresponding author. Tel.: +82-2-705-8439; fax: +82-2-701-0967;
e-mail: kangj@ccs.sogang.ac.kr
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00838-8

306
J. Kang et al. / Tetrahedron: Asymmetry 14 (2003) 305–315
during the reactions (Fig. 2). The primary concern here
is that Lewis acid coordination to enones is usually
nonselective since the two lone pairs of the carbonyl
oxygen are in similar steric and electronic environ-
ments, which eventually leads to poor levels of enantio-
control (Fig. 2).
With this in mind, binaphthols modified by varying the
chain length between the binaphthol core and the Cu-
binding site were prepared from bis(methoxymethyl)
ethers and used in the conjugate addition of diethylzinc
to enones and nitroalkenes.
We synthesized these ligands from the MOM-protected
BINOL (9 in Scheme 1), which could introduce many
electrophiles to the a-position to the hydroxy group of
BINOL.13 The route for the synthesis of these ligands is
described in Scheme 1.
2.2. Asymmetric 1,4-addition reactions
With these bissulfides in hand, extensive optimization
studies were carried out. Initially, optimization experi-
ments on the ligand structure was conducted with 2-
cyclohexen-1-one as a model substrate, copper triflate
(Cu(OTf)2) as a catalyst metal salt, and diethyl ether as
a solvent. Thus, a solution of the ligand in ether at rt
was added to a stirred suspension of Cu(OTf)2 in ether
and the mixture was stirred for 30 min. Et2Zn (neat; 1.5
equiv.) was added dropwise at 0°C, and the mixture
was stirred for a further 5 min. Subsequently, the
reaction mixture was cooled to the temperature indi-
cated, and 2-cyclohexen-1-one was added at the
required temperature. After the reaction was complete,
the mixture was worked up, and the product was
converted to the corresponding ketal with (2R,4R)-(−)-
pentanediol in the presence of a catalytic amount of
acid. Thus, sulfide ligands were shown to be better than
dithioacetals even though dithioacetals 8 with long
tethers did show some enantioselectivity (Table 1).
Figure 2.
Our theory was that, irrespective of the coordination
mode of the enone (i.e. metal syn or anti to the CꢀC
double bond), it may be possible to selectively attack
the double bond of the enone from different arms of a
binaphthyl skeleton. During this study, Woodward and
co-workers have published several papers on a concep-
tually similar approach using the sulfide complex 5,12
which, we believe, is operationally different from our
ligands.
The prior formation of aluminum binolate by adding
the exact amount of an alkylaluminum reagent such as
Me3Al and Me2AlCl (to increase the Lewis acidity) did,
Scheme 1. Synthesis of ligands.

J. Kang et al. / Tetrahedron: Asymmetry 14 (2003) 305–315
307
Table 1. Effect of side chain functionality (sulfide versus dithioacetal) in the Cu-catalyzed conjugate addition
Entry
Ligand
Cu(OTf)2 (equiv.)
Condition
Yield (%)a
ee (%)b
Conf.c
1
2
3
4
5
6
1
6
2
3
7
8
0.10
0.10
0.10
0.05
0.05
0.05
0°C/16 h
0°C/2 h
0°C/2 h
0°C/1 h
0°C/2 h
−15°C/2 h
86
12
95
91
16
41
0
0
69
65
11
56
–
–
R
R
R
R
a Isolated yield by flash column chromatography on silica gel.
b Enantiomeric excess was determined by GC analysis of the chiral acetal derived from (2R,4R)-(−)-pentanediol (HP-FFAP (25 m×0.32 mm); tR:
7.69 min (R), 8.05 min (S)).
c Absolute configuration was determined by comparison of the specific rotation with that reported in the literature.14
in fact, lead to lower enantioselectivity. Another funda-
mental question was whether the sequence of addition
of the reagents would affect the outcome of the reac-
tion. In fact, the order of addition did not affect the
enantioselectivity of the reaction (Table 2).
both the interaction of the Lewis acidic Zn centre with
the Lewis basic carbonyl oxygen and the coordination
of copper salts with the sulfide ligand, eventually show-
ing considerable solvent effects on enantioselectivity.
However, the use of highly polar and non-polar sol-
vents gave lower enantioselectivities. Thus, MTBE
(methyl tert-butyl ether) was found to be universally
optimum (Table 3).
Among the sulfides 1–4, the best ligands were the
C2-bridged ligands with stronger affinity for Cu, 2 and
3 (but not phenyl-substituted ligand 4). Between the
C2-bridged ligands, 2 and 3, the choice was ambiguous
since with cyclic enones the methylthio ligand 2 was
better than the t-butylthio ligand 3, but the trend was
reversed with acyclic enones (vide infra). And the opti-
mal mole ratio of the ligand to Cu salt was shown to be
<2. At ratios of >2 the enantioselectivity dropped sig-
nificantly, presumably because uncoordinated Cu salt
present in the reaction mixture would trigger the forma-
tion of racemic products via competitive non-enantiose-
lective reaction.
With these facts in hand, the effect source of Cu(I) was
studied using several salts, such as the commonly used
Cu(OTf)2, [Cu(MeCN)4]BF4, Cu(acac)2, CuO-t-Bu,
Cu(I) halides (Br or I) and several Cu(II) carboxylates.
Unfortunately, however, the effect of Cu salts was
substrate-dependent (vide infra). It is generally believed
that the reactive copper is, irrespective of the initial
form of Cu salt employed, Cu(I), which could be gener-
ated by reduction of Cu(II) in the reaction media. It is
interesting to note that near the completion of our
study, Alexakis also reported the dramatic effects of
Cu(II) acetate on the enantioselectivity of the conjugate
addition of diethylzinc in the presence of biphenol-
Initially, it was conceived that non-polar solvents were
preferable since coordinating solvents could disturb
Table 2. Mode of addition of reagents in the Cu-catalyzed conjugate addition of Et2Zn
Entry
Conditions
Yield (%)a
ee (%)b
24
Config.c
1
2
3
(1) Me2AlCl (0.05 equiv., rt, 1.6 h). (2) Cu(OTf)2 (rt, 1 h). (3) Substrate (−20°C). (4)
Et2Znd (−20°C to rt)
76
73
56
R
R
R
(1) Cu(OTf)2 (rt/1 h). (2) Et2Znd (−15°C/15 min). (3) −15°C/2 h
50
(1) Et2Znd (0°C/1 h). (2) Cu(OTf)2 (−15°C/10 min). (3) −15°C/2 h
49
a Isolated yield by flash column chromatography on silica gel.
b Enantiomeric excess was determined by GC analysis of the chiral acetal derived from (2R,4R)-(−)-pentanediol (HP-FFAP (25 m×0.32 mm); tR:
7.69 min (R), 8.05 min (S)).
c Absolute configuration was determined by comparison of the specific rotation value with that reported in the literature.14
d Et2Zn (1.0 M in hexane) was used.

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J. Kang et al. / Tetrahedron: Asymmetry 14 (2003) 305–315
Table 3. Effect of solvent in the Cu-catalyzed conjugate addition
Entrya
Solvent
Condition
Yield (%)b
ee (%)c
Config.d
1
2
3
4
Toluene
MC
Ether
−15°C/2 h
0°C/2 h
0°C/2 h
73
75
95
95
50
16
69
72
R
R
R
R
MTBE
0°C/2 h
a Et2Zn (1.0 M in hexane) was used.
b Isolated yield by flash column chromatography on silica gel.
c Enantiomeric excess was determined by GC analysis of the chiral acetal derived from (2R,4R)-(−)-pentanediol (FFAP (25 m×0.32 mm); tR: 7.69
min (R), 8.05 min (S)).
d Absolute configuration was determined by comparison of the specific rotation value with that reported in the literature.14
derived phosphoramidites,15 although the substrate-spe-
cificity in their case is somewhat opposite from that
seen in this study: In our case Cu(OAc)2 gave the best
enantioselectivity where applicable of the Cu(II) car-
boxylates employed (acetate, benzoate, and 2-
ethylhexanoate).
As for the mechanism of this reaction, nothing is clear
yet. In view of the strange preference of cyclic sub-
strates towards the methylthio ligand 2-Cu(OTf)2 com-
bination and that of acyclic substrates towards the
Table 4. Cu-catalyzed conjugate addition of Et2Zn to var-
ious enones (at 0°C for 2 h)
From this rather crude optimization (due to the unfor-
tunate non-generality of this type of reaction), the
following method was developed: to a stirred suspen-
sion of the Cu salt (2 mol%) in an inert solvent was
added a ligand (2.4 mol%, 20% excess to eliminate the
possibility of uncomplexed Cu salt) in the same solvent
at rt. The amount of solvent was adjusted so that the
final concentration of the substrate was 0.1 M. And the
mixture was stirred for 30 min. Et2Zn (neat; 3.0 equiv.)
was added dropwise at 0°C and the mixture was stirred
for a further 5 min. Subsequently, the reaction mixture
was cooled to the temperature indicated (0°C for
enones and −30°C for nitroolefins), and the enone (or
nitroolefin) was added. Usually, reaction times of 2 h
were sufficient for complete consumption of the starting
materials in both cases. As can be seen from Table 4,
the MTBE solvent gave the best enantioselectivity and
reactivity. The salt effect was rather dramatic: for cyclic
enones such as 2-cyclohexenone and 2-cycloheptenone,
a combination of ligand 2 and Cu(OTf)2 gave better
enantioselectivity while the ligand 3-Cu(OAc)2 combi-
nation gave better enantioselectivity with an acyclic
enone (chalcone). Additionally, the enantioselectivity
with chalcone (96% ee) using the ligand 3-Cu(OAc)2
system was much better than the much heralded binol
phosphorimidite protocol of Feringa and Alexakis
(71% ee), while the enantioselectivity with our system
was inferior. (85% ee versus 99% ee in case of 2-cyclo-
hexenone.) In the case of chalcone, the arylsulfide lig-
and (4 in Fig. 3) showed moderate enantioselectivity
under the reaction conditions described above (74%
yield, 22% ee).
Exactly the same trend was observed with acyclic
nitroolefins: The t-butylthio ligand 3 and Cu(OAc)2
combination gave better enantioselectivity than the
methylthio ligand 2 (Table 5).
Figure 3.

J. Kang et al. / Tetrahedron: Asymmetry 14 (2003) 305–315
309
Table 5. Cu-catalyzed conjugate addition of Et2Zn to var-
ious nitroolefins (at −30°C, 2 h)
4. Experimental
4.1. Preparation of (R)-2,2%-bis(methoxymethoxy)-(1,1%)-
binaphthalenyl-3,3%-dicarboxaldehyde, 10
To a stirred solution of (R)-2,2%-bis(methoxymethoxy)-
(1,1%)-binaphthalenyl (3.50 g, 9.35 mmol in 156 mL
ether) was added n-BuLi (12.5 mL, 28.1 mmol, 2.23 M
in hexane) at 0°C and stirred for 3 h at room tempera-
ture. The resulting mixture was cooled to 0°C and
diluted with anhydrous THF (93.5 mL). To the result-
ing dark brown solution was added N,N-dimethylfor-
mamide (2.75 mL, 37.4 mmol) at 0°C and the resulting
solution was warmed to room temperature. The reac-
tion mixture was quenched by addition of a saturated
NaHCO3 solution and extracted with diethyl ether. The
combined organic phase was dried with Na2SO4,
filtered and concentrated under reduced pressure. The
product was purified with flash column chromatogra-
phy using 20% EtOAc/n-hexane as yellow solid (2.857
g). Yield 71%. [h]D25 −51.7 (c 1.0, CHCl3). Mp 114–
118°C. IR (KBr) 2988, 2904, 2824, 1691, 1618, 1582,
1
1497, 1448, 1346, 1154, 952 cm−1. H NMR (500 MHz,
CDCl3): l 2.88 (s, 6H, OCH3), 4.69 (d, J=6.2 Hz, 2H,
OCH2O), 4.73 (d, J=6.2 Hz, 2H, OCH2O), 7.22 (dd,
J=8.5 Hz, J%=0.8 Hz, 2H, aromatic), 7.41–7.45 (m,
2H, aromatic), 7.51–7.54 (m, 2H, aromatic), 8.08 (d,
J=8.2 Hz, 2H, aromatic), 8.62 (s, 2H, aromatic), 10.5
(s, 2H, CHO). 13C NMR (125.7 MHz, CDCl3): l 56.99,
100.59, 126.08, 126.26, 128.89, 129.61, 130.06, 130.29,
132.28, 136.69, 154.03, 190.63. MS (EI, 70 eV) m/z: 430
(M+), 354 (M−C3H8O2). Anal. calcd for C26H22O6: C,
72.55; H, 5.15. Found: C, 72.56; H, 5.28%.
t-butylthio ligand 3-Cu(OAc)2 combination, the Cu salt
effect is approximately opposite to the Alexakis’
results.9 However, we are pleased to present evidence
that supports our initial hypothesis that the ligands
were designed in such a way that the enones and
alkylcopper species were brought together: with 2-
cyclohexenone itself in the presence of Cu(OTf)2,
unsubstituted binol itself gave only 7% ee of (3R)-ethyl-
cyclohexanone, and the monosubstituted binol sulfide
(Fig. 4), which was prepared analogously, gave (3R)-
ethylcyclohexanone with ee of only 74%.
4.2. Preparation of (R)-3,3%-bis(hydroxymethyl)-2,2%-
bis(methoxymethoxy)-(1,1%)-binaphthalenyl, 11
To a stirred solution of 10 (1.82 g, 4.22 mmol in 10.6
mL THF and 10.6 mL MeOH) was added sodium
borohydride (0.959 g, 25.3 mmol) portionwisely at 0°C
and stirred at rt for 12 h. After completion of reaction
the resulting mixture was cooled to 0°C. The solution
was quenched by addition of cold water (1.06 mL) and
the solvent was removed under reduced pressure. The
aqueous phase was extracted with ethyl acetate. The
combined solution was dried with Na2SO4, filtered and
concentrated under reduced pressure. The crude
product was purified by flash column chromatography
using 50% EtOAc/n-hexane (1.83 g). Yield 100%. [h]D25
−159.3 (c 1.0, CHCl3). IR (neat) 3423, 3055, 2837, 1357,
3. Conclusion
In conclusion, new BINOL-based thioether ligands
were developed for the enantioselective conjugate addi-
tion of alkylzinc reagents to acyclic, cyclic unsaturated
ketones and nitroolefins. The last few decades have
witnessed the proliferation of the development of phos-
phorus ligands for asymmetric conjugate addition reac-
tions of organocopper reagents. We reported herein
some new thioether ligands based on the sulfur-copper
affinity, especially, the reaction with trans-chalcone,
which gave rise to excellent results (96.3% ee and 91%
yield).
1
1265, 1151, 976 cm−1. H NMR (500 MHz, CDCl3): l
3.12 (s, 6H, OCH3), 3.39 (br s, 2H, OH), 4.39 (dd,
J=14.2 Hz, J%=6.2 Hz, 4H, CH2OH), 4.77 (d, J=12.6
Hz, 2H, OCH2O), 7.94 (s, 2H, aromatic), 4.91 (d,
J=12.6 Hz, 2H, OCH2O), 7.07–7.09 (m, 2H, aromatic),
7.17–7.21 (m, 2H, aromatic), 7.34–7.38 (m, 2H, aro-
matic), 7.83 (d, J=8.1 Hz, 2H, aromatic). 13C NMR
(125.7 MHz, CDCl3): l 57.12, 61.87, 99.32, 125.15,
125.44, 125.73, 126.85, 128.19, 129.75, 130.96, 133.75,
134.54, 153.13. MS (EI, 70 eV) m/z: 432 (M+−2), 406
(M−CH3O), 391 (M−C2H5O). Anal. calcd for
C26H26O6: C, 71.87; H, 6.03. Found: C, 70.79; H,
6.35%.
Figure 4.

310
J. Kang et al. / Tetrahedron: Asymmetry 14 (2003) 305–315
4.3. Preparation of (R)-2,2%-bis(methoxymethoxy)-3,3%-
bis(methylsulfanylmethyl)-(1,1%)-binaphthalenyl, 12
BF3·OEt2 (3.05 mL, 24.03 mmol) and stirred for 1 h at
−78°C. The reaction mixture was quenched by addition
of saturated NaHCO3 solution and extracted with
diethyl ether. The combined organic phase was dried
with Na2SO4, filtered and concentrated under reduced
pressure. The product was purified with flash column
chromatography using 70% EtOAc/n-hexane (1.68 g).
Yield 45%. IR (neat) 3384, 3057, 2935, 2884, 1497,
In a 50 mL round-bottomed flask was placed 11 (1.83
g, 4.21 mmol), dissolved with THF (21.1 mL) and
cooled to 0°C. To that reaction mixture were added
tributylphosphine (3.15 mL, 12.6 mmol) and dimethyl
disulfide (1.14 mL, 12.6 mmol) successively. Finally the
solution was heated under reflux for 40 h. The reaction
mixture was treated with H2O and the aqueous phase
was extracted ether. The combined organic phase was
dried with Na2SO4, filtered and concentrated under
reduced pressure. The crude product was purified with
flash column chromatography using 10% EA/n-hexane
1
1356, 1236, 1156, 921, 752 cm−1. H NMR (300 MHz,
CDCl3): l 2.15 (br s, 2H, OH), 2.99 (s, 6H, OCH3),
3.11–3.30 (m, 4H, CH2OH), 4.03 (t, J=6.3 Hz, 4H,
ArCH2), 4.40 (d, J=5.8 Hz, 2H, OCH2O), 4.54 (d,
J=5.8 Hz, 2H, OCH2O), 7.13–7.26 (m, 4H, aromatic),
7.39–7.42 (m, 2H, aromatic), 7.83–7.87 (m, 4H, aro-
matic). 13C NMR (125.7 MHz, CDCl3): l 34.41, 56.70,
63.22, 99.01, 125.14, 125.27, 125.91, 126.14, 127.52,
129.99, 130.86, 132.37, 133.17, 153.21. MS (EI, 70 eV)
m/z: 462 (M+), 398 (M−C2H4O2), 338 (M−C4H12O4).
Anal. calcd for C28H30O6: C, 72.71; H, 6.54. Found: C,
72.74; H, 6.62%.
1
(1.22 g). Yield 59%. H NMR (300 MHz, CDCl3): l
1.90 (s, 2H, aromatic), 2.15 (s, 6H, SCH3), 2.92 (s, 6H,
OCH3), 4.04 (dd, J=13.5 Hz, J%=26.9 Hz, 4H,
CH2SCH3), 4.50 (d, J=5.5 Hz, 2H, OCH2O), 4,65 (d,
J=5.8 Hz, 2H, OCH2O), 7.15–7.24 (m, 2H, aromatic),
7.34–7.40 (m, 2H, aromatic), 7.85 (d, J=8.2 Hz, 2H,
aromatic). 13C NMR (125.7 MHz, CDCl3): l 15.59,
33.76, 56.71, 99.28, 125.18, 125.66, 126.01, 126.36,
127.71, 129.80, 130.59, 131.67, 133.49, 152.69.
4.6. Preparation of (R)-2,2%-bis(methoxymethoxy)-3,3%-
bis(2-methylsulfanylethyl)-(1,1%)binaphthalenyl, 14
4.4. Preparation of (R)-3,3%-bis(methylsulfanylmethyl)-
(1,1%)-binaphthalenyl-2,2%-diol, 1
In a 50 mL round-bottomed flask was placed 13 (0.409
g, 0.884 mmol), dissolved with THF (8.84 mL) and
cooled to 0°C. To that reaction mixture were added
tributylphosphine (0.661 mL, 2.65 mmol) and dimethyl
disulfide (0.239 mL, 2.65 mmol) successively. Finally
the solution was heated under reflux for 40 h. The
reaction mixture was treated with H2O and the aqueous
phase was extracted ether. The combined organic phase
was dried with Na2SO4, filtered and concentrated under
reduced pressure. The crude product was purified with
flash column chromatography using 10% EA/n-hexane
(0.240 g). Yield 52%. [h]2D5 −130.0 (c 0.34, CHCl3). IR
(neat) 3056, 2915, 2826, 1594, 1497, 1430, 1356, 1236,
1157, 1068, 978, 753 cm−1. 1H NMR (300 MHz,
CDCl3): l 7.83–7.85 (m, 4H, aromatic), 7.35–7.41 (m,
2H, aromatic), 7.11–7.39 (m, 4H, aromatic), 4.52 (d,
J=5.8 Hz, 2H, OCH2O), 4.41 (d, J=5.8 Hz, 2H,
OCH2O), 3.10–3.35 (m, 4H, ArCH2), 2.85–3.06 (m, 4H,
CH2SMe), 2.98 (s, 6H, OCH3), 2.20 (s, 6H, SCH3). 13C
NMR (125.7 MHz, CDCl3): l 153.18, 134.03, 133.24,
130.78, 129.44, 127.51, 126.05, 125.96, 125.22, 125.03,
99.06, 56.76, 34.60, 31.52, 15.64. MS (EI, 70 eV) m/z:
522 (M+), 446 (M−C3H8O2). Anal. calcd for
C30H34O4S2: C, 68.93; H, 6.56; S, 12.27. Found: C,
68.64; H, 6.77, S, 12.21.
In a 50 mL round-bottomed flask were placed 12 (1.22
g, 2.46 mmol) and MC (14.6 mL). This resulting mix-
ture was cooled to −78°C and MeSH (1.19 g, 24.6
mmol in 10.0 mL MC) and BF3·OEt2 (0.094 mL, 0.74
mmol) were added successively. The cooling bath was
removed and the reaction mixture was stirred for 12 h
at rt. After the completion of reaction, saturated
NaHCO3 solution was added to that solution. The
organic phase was extracted with MC and the com-
bined organic phase was washed with brine. The crude
product was purified with flash column chromatogra-
phy using 10% EA/n-hexane (0.926 g). Yield 92%. [h]D25
+105.5 (c 1.0, CHCl3). Mp: 103–105°C. IR (KBr) 3354,
1
3058, 2920, 1624, 1455, 1208, 1142, 753 cm−1. H NMR
(500 MHz, CDCl3): l 2.11 (s, 6H, SCH3), 3.96 (s, 4H,
CH2SCH3), 5.58 (s, 2H, OH), 7.06 (d, 2H, J=8.4 Hz,
aromatic), 7.22–7.25 (m, 2H, aromatic), 7.31–7.35 (m,
2H, aromatic), 7.83 (d, J=7.7 Hz, aromatic), 7.87 (s,
2H, aromatic). 13C NMR (125.7 MHz, CDCl3): l 15.31,
33.73, 112.47, 124.20, 124.19, 126.39, 127.06, 128.04,
129.04, 130.67, 132.84, 151.24. MS (EI, 70 eV) m/z: 406
(M+), 358 (M−CH4S), 311 (M−C2H7S2). Anal. calcd for
C24H22O2S2: C, 70.90; H, 5.45; S, 15.77. Found: 70.96,
H, 5.47; S, 15.70%.
4.7. Preparation of (R)-3,3%-bis(2-methylsulfanylethyl)-
(1,1%)-binaphthalenyl-2,2%-diol, 2
4.5. Preparation of (R)-3,3%-bis(2-hydroxyethyl)-2,2%-
bis(methoxymethoxy)-(1,1%)-binaphthalenyl, 13
In a 25 mL round-bottomed flask was charged 14
(0.120 g, 0.230 mmol) and dissolved with THF (2.30
mL). To that solution was added catalytic amount of
6N HCl and heated under reflux for 12 h. The resulting
solution was evaporated under reduced pressure and
extracted with Et2O. The combined organic phase was
dried with Na2SO4, filtered and concentrated under
reduced pressure. The crude product was purified with
flash column chromatography using 10% EA/n-hexane
(0.097 g). Yield 96%. [h]2D5 +66.5 (c 1.0, CHCl3). Mp:
To a stirred solution of (R)-2,2%-bis(methoxymethoxy)-
(1,1%)-binaphthalenyl (3.000 g, 8.012 mmol in 133.5 mL
ether) was added n-BuLi (11.1 mL, 24.04 mmol, 2.17 M
in hexane) at 0°C and stirred for 3 h at room tempera-
ture. The resulting mixture was cooled to −78°C and
diluted with anhydrous THF (80.12 mL). To the result-
ing dark brown solution was added ethylene oxide (5.83
mL, 32.04 mmol, 5.50 M in ether), followed by

J. Kang et al. / Tetrahedron: Asymmetry 14 (2003) 305–315
311
122°C–124°C. IR (KBr) 3399, 3058, 2945, 2917, 1624,
1504, 1449, 1414, 1392,1211, 1131, 1016 cm−1. 1H NMR
(300 MHz, CDCl3): l 7.84–7.87 (m, 4H, aromatic),
7.32–7.39 (m, 2H, aromatic), 7.22–7.29 (m, 2H, aro-
matic), 7.05–7.09 (m, 2H, aromatic), 5.22 (s, 2H, OH),
3.16–3.22 (m, 4H, ArCH2), 2.89–2.94 (m, 4H,
CH2SCH3), 2.17 (s, 6H, SCH3). 13C NMR (125.7 MHz,
CDCl3): l 151.61, 132.40, 130.73, 129.34, 129.20,
127.91, 126.84, 124.10, 124.00, 110.98, 34.02, 31.36,
15.36. MS (EI, 70 eV) m/z: 434 (M+), 373 (M−C2H5S),
325 (M−C3H9SO2). Anal. calcd for C26H26O2S2: C,
71.85; H, 6.03; S, 14.76. Found: C, 71.81; H, 6.02, S,
14.49%.
CH2SBut), 3.10–3.30 (m, 4H, ArCH2), 4.43 (d, J=5.8
Hz, 2H, OCH2O), 4.52 (d, J=5.8 Hz, 2H, OCH2O),
7.12–7.26 (m, 4H, aromatic), 7.35–7.41 (m, 2H, aro-
matic), 7.82–7.86 (m, 4H, aromatic). 13C NMR (125.7
MHz, CDCl3): l 28.84, 31.06, 31.92, 42.20, 56.78,
99.03, 124.96, 127.53, 125.98, 129.31, 130.77, 133.22,
134.44, 153.20. MS (EI, 70 eV) m/z: 606 (M+), 474
(M−C6H12SO), 430 (M−C10H24O2). Anal. calcd for
C36H46O4S2: C, 71.25; H, 7.64; S, 10.57. Found: C,
69.27; H, 8.06, S, 9.44%.
4.10. Preparation of (R)-3,3%-bis(2-t-butylsulfanylethyl)-
(1,1%)-binaphthalenyl-2,2%-diol, 3
In a 25 mL round-bottomed flask were placed 16 (0.581
g, 0.957 mmol) and MC (6.00 mL). This resulting
mixture was cooled to −78°C and MeSH (0.460 g, 9.57
mmol in 3.57 mL MC) and BF3·OEt2 (0.036 mL, 0.287
mmol) were added successively. The cooling bath was
removed and the reaction mixture was stirred for 12 h
at rt. After the completion of reaction, saturated
NaHCO3 solution was added to that solution. The
organic phase was extracted with MC and the com-
bined organic phase was washed with brine. The crude
product was purified with flash column chromatogra-
phy using 10% EA/n-hexane (0.464 g). Yield 94%. [h]D25
+60.2 (c 1.0, CHCl3). Mp: 129–132°C. IR (KBr) 3528,
4.8. Preparation of (R)-3,3%-bis(2-bromoethyl)-2,2%-bis-
(methoxymethoxy)-(1,1%)-binaphthalenyl, 15
To a 50 mL round-bottomed flask were charged 13
(0.759 g, 1.64 mmol), CBr4 (1.632 g, 4.92 mmol), and
2,6-lutidine (0.955 mL, 8.20 mmol) in 16.4 mL MC was
added triphenylphosphine (1.075 g, 4.10 mmol) at 0°C
and stirred at rt for 12 h. After completion of reaction,
reaction mixture was quenched with water and
extracted with methylene chloride. The combined
organic phase was dried with Na2SO4, filtered and
concentrated under reduced pressure. The resulting
solid was dissolved with cold diethyl ether and insoluble
solid was filtered off. The product was purified with
flash column chromatography using 10% EtOAc/n-hex-
ane (0.846 g). Yield 88%. [h]2D5 +116.3 (c 0.27, CHCl3).
IR (KBr) 3055, 2955, 2824, 1497, 1358, 1203, 969, 754,
1
3320, 2960, 2938, 2897, 1624, 1210, 750 cm−1. H NMR
(300 MHz, CDCl3): l 1.34 (s, 18H, t-Bu), 2.95 (t,
J=7.7 Hz, 4H, CH2SBut), 3.16 (t, J=7.7 Hz, 4H,
ArCH2), 5.23 (s, 2H, OH), 7.06–7.10 (m, 2H, aromatic),
7.22–7.28 (m, 2H, aromatic), 7.32–7.38 (m, 2H, aro-
matic), 7.84–7.87 (m, 4H, aromatic). 13C NMR (125.7
MHz, CDCl3): l 28.21, 31.04, 32.42, 42.33, 111.04,
124.03, 124.05, 126.74, 127.92, 129.32, 129.50, 130.69,
132.41, 151.65. MS (EI, 70 eV) m/z: 518 (M+), 406
(M−C8H16), 359 (M−C9H19S). Anal. calcd for
C32H28O2S2: C, 74.09; H, 7.38; S, 12.36. Found: C,
74.01; H, 7.38, S, 12.36%.
1
555 cm−1. H NMR (300 MHz, CDCl3): l 3.07 (s, 6H,
OCH3), 3.34–3.62 (m, 4H, CH2Br), 3.73–3.84 (m, 4H,
ArCH2), 4.38 (d, J=5.8 Hz, 2H, OCH2O), 4.46 (d,
J=5.8 Hz, 2H, OCH2O), 7.12–7.15 (m, 2H, aromatic),
7.21–7.27 (m, 2H, aromatic), 7.37–7.44 (m, 2H, aro-
matic), 7.84–7.88 (m, 4H, aromatic). 13C NMR (125.7
MHz, CDCl3): l 32.24, 35.28, 56.95, 99.26, 125.12,
125.24, 125.87, 126.48, 127.72, 130.26, 130.65, 132.32,
133.45, 153.33. MS (EI, 70 eV) m/z: 514 (M+−C3H8O2+
4), 512 (M+−C3H8O2+2), 510 (M+−C3H8O2). Anal.
calcd for C28H28Br2O4: C, 57.16; H, 4.80. Found: C,
57.13; H, 4.84%.
4.11. Preparation of (R)-2,2%-bis(methoxymethoxy)-3,3%-
bis(2-phenylsulfanylethyl)-(1,1%)-binaphthalenyl, 17
In a 25 mL round-bottomed flask was charged 13
(0.300 g, 0.649 mmol) and dissolved with THF (6.46
mL). To that resulting solution were added tri-
butylphosphine (0.485 mL, 1.95 mmol) and diphenyl-
disulfide (0.426 g, 1.95 mmol) at rt and heated under
reflux for 12 h. The reaction mixture was treated with
H2O and the aqueous phase was extracted ether. The
combined organic phase was dried with Na2SO4,
filtered and concentrated under reduced pressure. The
crude product was purified with flash column chro-
matography using 10% EA/n-hexane (0.362 g). Yield
86%. 1H NMR (300 MHz, CDCl3): l 2.91 (s, 6H,
OCH3), 3.14–3.45 (m, 8H, ArCH2CH2Ph), 4.36 (d, J=
5.8 Hz, 2H, OCH2O), 4.45 (d, J=5.8 Hz, 2H, OCH2O),
7.11–7.52 (m, 16H, aromatic), 7.79–7.85 (m, 4H, aro-
matic). 13C NMR (125.7 MHz, CDCl3): l 31.57, 33.96,
56.72, 99.04, 125.07, 125.16, 125.96, 126.14, 127.53,
128.91, 129.36, 129.63, 130.72, 133.28, 133.66, 136.40,
153.21. MS (EI, 70 eV) m/z: 646 (M+), 570 (M−
C3H8O2). Anal. calcd for C40H38O4S2: C, 74.27; H, 5.92;
S, 9.91. Found: C, 66.01; H, 5.82, S, 8.50%.
4.9. Preparation of (R)-3,3%-bis(2-t-butylsulfanylethyl)-
2,2%-bis(methoxymethoxy)-(1,1%)-binaphthalenyl, 16
In a 25 mL round-bottomed flask sodium (0.070 g, 3.06
mmol) was dissolved in 10.2 mL MeOH and t-BuSH
(0.402 mL, 3.57 mmol) was added at rt dropwisely. To
this resulting solution was added 15 (0.600 g, 1.02
mmol) dissolved in THF as one portion at rt and
stirred for 18 h. After the completion of reaction was
added water to the reaction mixture and the solvent
was removed under reduced pressure. The aqueous
phase was extracted with ethyl ether and the combined
organic phase was dried with Na2SO4, filtered, and
concentrated under reduced pressure. The crude
product was purified with flash column chromatogra-
phy using 5% EA/n-hexane (0.581 g). Yield 94%. IR
(neat) 3055, 2899, 2863, 2825, 1457, 1362, 1069, 922,
1
750 cm−1. H NMR (300 MHz, CDCl3): l 1.37 (s, 18H,
t-Bu), 2.99 (s, 6H, OCH3), 2.90–3.10 (m, 4H,

312
J. Kang et al. / Tetrahedron: Asymmetry 14 (2003) 305–315
4.12. Preparation of (R)-3,3%-bis(2-phenylsulfanylethyl)-
(1,1%)-binaphthalenyl-2,2%-diol, 4
and to this solution was added triphenylphosphine
(0.226 g, 0.863 mmol) at 0°C and stirred at rt for 2 h.
After completion of reaction, reaction mixture was
quenched with water and extracted with methylene
chloride. The combined organic phase was dried with
Na2SO4, filtered and concentrated under reduced pres-
sure. The resulting solid was dissolved with cold diethyl
ether and insoluble solid was filtered off. The product
was used for the next step without further purification.
In a 10 mL round-bottomed flask were placed 17 (0.100
g, 0.155 mmol) and MC (1.00 mL). This resulting
mixture was cooled to −78°C and MeSH (0.0746 g, 1.55
mmol in 0.55 mL MC) and BF3·OEt2 were added
successively. The cooling bath was removed and the
reaction mixture was stirred for 12 h at rt. After the
completion of reaction, saturated NaHCO3 solution
was added to that solution. The organic phase was
extracted with MC and the combined organic phase
was washed with brine. The crude product was purified
with flash column chromatography (10% EA/n-hex-
ane). Yield 81%. [h]D25 +67.3 (c 1.0, CHCl3). IR (KBr)
3508, 3057, 2927, 1624, 1480, 1387, 1212, 1093, 1024,
739 cm−. 1 1H NMR (300 MHz, CDCl3): l 3.19–3.26 (m,
4H, CH2SPh), 3.31–3.38 (m, 4H, ArCH2), 5.14 (s, 2H,
OH), 7.03–7.41 (m, 16H, aromatic), 7.81–7.85 (m, 4H,
aromatic). 13C NMR (125.7 MHz, CDCl3): l 24.69,
26.08, 103.86, 116.96, 117.17, 118.80, 119.96, 120.94,
121.74, 121.87, 121.92, 121.98, 122.33, 124.09, 125.41,
144.57. MS (EI, 70 eV) m/z: 558 (M+), 448 (M−C6H6S),
325 (M−C13H13S2). Anal. calcd for C36H30O2S2: C,
77.38; H, 5.41; S, 11.48. Found: C, 74.67; H, 5.73, S,
12.91%.
To
a
stirred solution of (bismethylsulfanyl-
methyl)trimethylsilane (0.249 g, 1.38 mmol) in 3.45 mL
of THF was added n-BuLi (2.31 mL, 2.23 M in hexane,
1.04 mmol) at −78°C and slowly warmed to 0°C. The
solution was stirred for 10 min at that temperature and
cooled again to −78°C. To the resulting solution was
added the product (dissolved in THF) obtained above.
The reaction was quenched with H2O and extracted
with ether. The organic phase was dried with Na2SO4
and filtered. The solution was concentrated under
reduced pressure and the crude product was purified
with flash column chromatography using 5% EtOAc/n-
hexane (0.225 g). Yield 74%. 1H NMR (300 MHz,
CDCl3): l 0.04 (s, 18H, TMS), 1.93 (s, 6H, SCH3), 2.01
(s, 6H, SCH3), 2.17 (s, 6H, OCH3), 3.02 (s, 4H, CH2)
4.27–4.36 (m, 4H, OCH2O), 6.92–6.95 (m, 2H, aro-
matic), 7.02–7.08 (m, 2H, aromatic), 7.20–7.26 (m, 2H,
aromatic), 7.74 (d, J=6.9 Hz, 2H, aromatic) 8.31 (s,
2H, aromatic).
4.13. Preparation of (R)-3,3%-bis(bis(methylsulfanyl)-
methyl)-(1,1%)-binaphthalenyl-2,2%-diol, 6
4.15. Preparation of (R)-3,3%-bis(2,2-bis(methylsulfanyl-
In a 100 mL round-bottomed flask were placed 10 (1.88
g, 4.37 mmol) and methylene chloride (33.7 mL). This
resulting mixture was cooled to −78°C and MeSH (2.10
g, 43.7 mmol in 10.0 mL MC) and BF3·OEt2 (0.166 mL,
1.31 mmol) were added successively. The cooling bath
was removed and the reaction mixture was stirred for
12 h at rt. After the completion of reaction, saturated
NaHCO3 solution was added to that solution. The
organic phase was extracted with MC and the com-
bined organic phase was washed with brine. The crude
product was purified with flash column chromatogra-
phy using 10% EA/n-hexane (1.36 g). Yield 62%. [h]D25
+61.5 (c 1.0, CHCl3). Mp: 98°C. IR (KBr) 3489, 3057,
ethyl))-2,2%-bis(methoxymethoxy)-(1,1%)-binaphthalenyl,
20
To a stirred solution 19 (0.070 g, 0.092 mmol) in 0.922
mL of THF was added TBAF (0.922 mL, 1.0 M in
THF) at rt and stirred for 30 min. 6N HCl was added
and stirred. The aqueous phase was extracted with ethyl
acetate. The organic phase was dried with Na2SO4 and
filtered. The solution was concentrated under reduced
pressure and the crude product was purified with flash
column chromatography using 10% EtOAc/n-hexane
1
(0.050 g). Yield 88%. H NMR (300 MHz, CDCl3): l
2.15 (s, 6H, SCH3), 2.18 (s, 6H, SCH3), 3.10 (s, 6H,
OCH3), 3.28 (dd, J=8.5 Hz, J=14.0 Hz, 2H, CH2) 3.50
(dd, J=6.9 Hz, J=14.0 Hz, 2H, CH2), 4.34 (dt, J=7.0
Hz, J=8.3 Hz, 2H, CH), 4.44 (dd, J=5.8 Hz, J=10.7
Hz, 4H, OCH2O), 7.13–7.24 (m, 4H, aromatic), 7.35–
7.41 (m, 2H, aromatic), 7.83–7.86 (m, 2H, aromatic).
1
2913, 1620, 1434, 1145, 961, 751 cm−1. H NMR (500
MHz, CDCl3): l 2.22 (s, 12H, SCH3), 5.44 (s, 2H,
CH(SCH3)2), 5.55 (s, 2H, OH), 7.06–7.08 (m, 2H, aro-
matic), 7.27–7.31 (m, 2H, aromatic), 7.37–7.40 (m, 2H,
aromatic), 7.91 (d, J=8.1 Hz, 2H, aromatic), 8.15 (s,
2H, aromatic). 13C NMR (125.7 MHz, CDCl3): l 14.87,
50.06, 112.14, 124.05, 124.42, 127.60, 128.41, 128.56,
129.36, 132.73, 149.79. MS (EI, 70 eV) m/z: 451 (M−
CH3S), 403 (M−C2H7S2), 389 (M−C3H10S2). Anal. calcd
for C26H26O2S4: C, 62.61; H, 5.25; S, 25.72. Found: C,
62.67; H, 6.57; S, 25.19%.
4.16. Preparation of (R)-3,3%-bis-(2,2-bis(methylsulfanyl)
ethyl)-(1,1%)-binaphthalenyl-2,2%-diol, 7
In a 25 mL round-bottomed flask were placed 20 (0.147
g, 0.239 mmol) and MC (1.4 mL). This resulting mix-
ture was cooled to −78°C and MeSH (0.115 g, 2.39
4.14. Preparation of (R)-3,3%-bis(2,2-bis(methylsulfanyl)-
2-trimethylsilanylethyl)-2,2%-bis(methoxymethoxy)-(1,1%)-
binaphthalenyl, 19
mmol in 1.0 mL MC) and BF3·OEt2 were added succes-
sively. The cooling bath was removed and the reaction
mixture was stirred for 12 h at rt. After the completion
of reaction, saturated NaHCO3 solution was added to
that solution. The organic phase was extracted with
MC and the combined organic phase was washed with
brine. The crude product was purified with flash
In a 50 mL round-bottomed flask were charged 11
(0.150 g, 0.345 mmol), CBr4 (0.345 g, 1.03 mmol),
2,6-lutidine (0.202 mL, 1.73 mmol) and 3.45 mL MC

J. Kang et al. / Tetrahedron: Asymmetry 14 (2003) 305–315
313
column chromatography using 10% EA/n-hexane
OCH2O), 4.54 (d, J=5.7 Hz, 2H, OCH2O), 7.11–7.24
(m, 4H, aromatic), 7.34–7.41 (m, 2H, aromatic), 7.81–
7.84 (m, 4H, aromatic). 13C NMR (125.7 MHz,
CDCl3): l 13.90, 24.75, 35.38, 53.66, 54.37, 99.19,
125.22, 126.14, 127.65, 129.36, 134.90, 153.09. MS (EI,
70 eV) m/z: 550 (M+−C3H8O3).
1
(0.101 g). Yield 80%. [h]2D5 +60.8 (c 0.12, CHCl3). H
NMR (500 MHz, CDCl3): l 2.16 (m, 12H, SCH3), 3.37
(qd, J=7.6 Hz, J=13.7 Hz, 4H, CH2), 4.24 (t, J=7.5
Hz, 2H, CH), 5.39 (s, 2H, OH) 7.09–7.11 (m, 2H,
aromatic), 7.25–7.28 (m, 2H, aromatic), 7.34–7.38 (m,
2H, aromatic), 7.83–7.86 (m, 4H, aromatic).
4.19. Preparation of (R)-3,3%-bis(3,3-bis(methylsulfanyl)-
propyl)-(1,1%)-binaphthalenyl-2,2%-diol, 8
4.17. Preparation of (R)-3,3%-bis(3-hydroxypropyl)-2,2%-
bis (methoxymethoxy)-(1,1%)-binaphthalenyl, 21
In a 25 mL round-bottomed flask was charged 23
(0.220 g, 0.342 mmol) and dissolved with THF (3.42
mL). To that solution was added catalytic amount of
6N HCl and heated to 70°C for 1 h. The resulting
solution was evaporated under reduced pressure and
extracted with Et2O. The combined organic phase was
dried with Na2SO4, filtered and concentrated under
reduced pressure. The crude product was purified with
flash column chromatography using 10% EA/n-hexane
(0.181 g). Yield 95%. [h]2D5 +57.7 (c 0.18, CHCl3). Mp:
106°C. IR (KBr) 3423, 2915, 1625, 1438, 1389, 1211,
To a stirred solution of (R)-2,2%-bis(methoxymethoxy)-
(1,1%)-binaphthalenyl (0.150 g, 0.400 mmol in 6.67 mL
ether) was added n-BuLi (0.597 mL, 1.20 mmol, 2.01 M
in hexane) at 0°C and stirred for 3 h at room tempera-
ture. The resulting mixture was cooled to −78°C and
diluted with anhydrous THF (4.00 mL). To the result-
ing dark brown solution was added trimethylene oxide
(0.104 mL, 1.60 mmol), followed by BF3·OEt2 (0.152
mL, 1.20 mmol) and stirred for 1 h at −78°C. The
reaction mixture was quenched by addition of saturated
NaHCO3 solution and extracted with diethyl ether. The
combined organic phase was dried with Na2SO4,
filtered and concentrated under reduced pressure. The
product was purified with flash column chromatogra-
phy using 70% EtOAc/n-hexane (0.101 g). Yield 51%.
[h]2D5 −136.9 (c 0.84, CHCl3). IR (neat) 3406, 2936,
1
1143, 750 cm−1. H NMR (300 MHz, CDCl3): l 2.13 (s,
12H, SCH3), 2.19–2.27 (m, 4H, ArCH2CH2), 3.16 (t,
J=7.7 Hz, 4H, ArCH2), 3.74 (t, J=7.1 Hz, 2H,
CH(SCH3)2), 5.18 (s, 2H, OH), 7.82–7.86 (m, 4H, aro-
matic), 7.05–7.07 (m, 2H, aromatic), 7.22–7.28 (m, 2H,
aromatic), 7.32–7.38 (m, 2H, aromatic). 13C NMR
(125.7 MHz, CDCl3): l 12.58, 29.34, 34.19, 54.06.
110.98, 123.98, 124.07, 126.73, 127.81, 129.36, 129.80,
130.51, 132.25, 151.68. MS (EI, 70 eV) m/z: 446 (M+−
C3H7S2). Anal. calcd for C30H34O2S4: C, 64.94; H, 6.18;
S, 23.12. Found: C, 64.72; H, 6.02, S, 23.22%.
1
2876, 1497, 1431, 1236, 1157, 753 cm−1. H NMR (300
MHz, CDCl3): l 1.95 (br s, 2H, OH), 2.02–2.07 (m, 4H,
CH2CH2CH2), 2.95 (s, 6H, OCH3), 2.90–3.15 (m, 4H,
ArCH2), 3.70–3.80 (br m, 4H, CH2OH), 4.38 (d, J=5.5
Hz, 2H, OCH2O), 4.53 (d, J=5.5 Hz, 2H, OCH2O),
7.13–7.26 (m, 4H, aromatic), 7.36–7.41 (m, 2H, aro-
matic), 7.81 (m, 4H, aromatic). 13C NMR (125.7 MHz,
CDCl3): l 27.00, 33.74, 56.81, 61.89, 77.46, 99.08,
125.05, 125.28, 125.94, 127.43, 129.25, 131.01, 132.97,
135.23, 153.06. MS (EI, 70 eV) m/z: 430 (M+−C3H7O).
Anal. calcd for C30H34O6: C, 73.45; H, 6.99. Found: C,
73.40; H, 7.01%.
4.20. General procedure for 1,4-addition to a,b-unsatu-
rated cyclic ketones
In a 25 mL round-bottomed flask was charged Cu salt
and diluted with solvent (half amount of total solvent
volume). To that solution was added ligand (diluted
with solvent) and stirred for 30 min at rt. Et2Zn (neat)
was added to the resulting solution at 0°C and stirred
for 5 min. The resulting yellowish brown solution was
immersed in bath for reaction temperature and enone
was added at reaction temperature dropwisely. The
reaction was monitored with TLC. After the comple-
tion of reaction 6N HCl was added to the reaction
mixture very carefully and warmed to room tempera-
ture. The aqueous phase was extracted with diethyl
ether and the combined organic phase was dried with
Na2SO4, filtered and evaporated. The crude product
was purified with flash column chromatography. The
enantiomeric excess of 3-ethylcyclohexan-1-one was
determined by GC analysis after conversion to the
chiral acetal; 8-ethyl-(2R,4R)-2,4-dimethyl-1,5-dioxas-
piro[5.5] undecane, which was prepared as described
below.
4.18. Preparation (R)-3,3%-bis(3,3-bis(methylsulfanyl)-
propyl)-2,2%-bis(methoxymethoxy)-(1,1%)-binaphthalenyl,
23
To a stirred solution of pyridinium chlorochromate
(11.0 g, 51.0 mmol) and Celite in 20.0 mL MC was
added 21 (1.47 g, 3.00 mmol in MC) at room tempera-
ture and the resulting mixture was heated under reflux
for 30 min. After completion of reaction the resulting
mixture was diluted with diethyl ether and the resulting
solid was filtered off. The filtrate was concentrated
under reduced pressure. The crude product was used
for the next reaction. In another round-bottomed flask
were charged the crude product and dimethyl disulfide
(0.707 g, 7.50 mmol) and tributylphosphine (2.24 mL,
9.00 mmol) was added. The reaction mixture was
stirred for 2 h and purified with flash column chro-
matography using 10% EtOAc/n-hexane (0.617 g).
1
1
Yield 32% (two step). H NMR (300 MHz, CDCl3): l
4.20.1. (R)-3-Ethylcyclohexanone. H NMR (300 MHz,
2,15 (s, 12H, SCH3), 2.20–2.40 (m, 4H, ArCH2CH2),
2.94 (s, 6H, OCH3), 3.05–3.30 (m, 4H, ArCH2), 3.73 (t,
J=7.1 Hz, 2H, CH(SCH3)2), 4.43 (d, J=5.5 Hz, 2H,
CDCl3): l 0.90 (t, J=7.4 Hz, 3H, CH3), 1.25–1.50 (m,
3H), 1.50–1.80 (m, 2H), 1.80–2.50 (m, 6H). MS (EI, 70
eV) m/z: 126 (M+), 97 (M−C2H5).

314
J. Kang et al. / Tetrahedron: Asymmetry 14 (2003) 305–315
4.21. Preparation of 8-ethyl-(2R,4R)-2,4-dimethyl-1,5-
dioxaspiro[5.5]undecane
4.23. General procedure for 1,4-addition to nitroolefins
In a 25 mL round-bottomed flask was charged Cu
salt and diluted with solvent (half amount of total
solvent volume). To that solution was added ligand
(diluted with solvent) and stirred for 30 min at rt.
Et2Zn (neat) was added to the resulting solution at
0°C and stirred for 5 min. The resulting yellowish
brown solution was immersed in bath for reaction
temperature and nitroolefin (diluted in small amount
of solvent) was added at reaction temperature drop-
wisely. The reaction was monitored with TLC. After
the completion of reaction 1:1 mixture of sat.
NH4Cl(aq) and 10% NH4OH was added to the reac-
tion mixture very carefully and warmed to room tem-
perature. The aqueous phase was extracted with
diethyl ether and the combined organic phase was
dried with Na2SO4, filtered and evaporated. The
crude product was purified with flash column chro-
matography.
In a 25 mL round-bottomed flask were charged 3-
ethylcyclohexan-1-one (0.269 g, 2.13 mmol), (2R,4R)-
(−)-pentanediol (0.310 g, 2.98 mmol), catalytic
amount of p-toluenesulfonic acid and benzene (7.1
mL). To that resulting mixture was added triethyl-
orthoformate at room temperature and stirred for 1
h. After the completion of reaction water was added
to that solution and the organic phase was extracted
with diethyl ether. The combined organic phase was
dried with Na2SO4 and filtered through the Celite
pad. The crude product was purified with flash
column chromatography (10% ether/n-hexane). 1H
NMR (300 MHz, CDCl3): l 0.87 (t, J=7.4 Hz, 3H,
CH3), 1.17–1.25 (m, 10H), 1.40–1.75 (m, 7H), 2.00–
2.10 (m, 2H), 3.85–4.13 (m, 2H). MS (EI, 70 eV)
m/z: 212 (M+), 183 (M−C2H5). GC resolution: HP-
FFAP (25 m×0.32 mm); oven temp.: 140°C, inj.
temp.: 250°C, det. temp.: 250°C, flow rate: 1.0 mL/
min; retention time: 7.69 min (R), 8.05 min (S).
4.23.1. (2S)-1-Nitro-2-phenylbutane. 1H NMR (300
MHz, CDCl3): l 0.82 (t, J=7.2 Hz, 3H, CH2CH3),
1.57–1.80 (m, 2H, CH2CH3), 3.29–3.40 (m, 1H, CH),
4.52–4.57 (m, 2H, CH2NO2), 7.15–7.35 (m, 5H, Ph).
MS (EI, 70 eV) m/z: 179 (M+), 132 (M−NO2), 104
(M−C2H5NO2), 77 (Ph). GC resolution: Chirasil-dex
CB (25 m×0.2 mm); oven temp.: 120°C, inj. temp.:
200°C, det. temp.: 200°C, flow rate: 1.0 mL/min;
retention time: 29.28 min (S), 30.48 min (S). HPLC
resolution: Chiralcel OD-H; Eluent 5% IPA/n-hexane;
flow rate: 0.5 mL/min; retention time: 23.82 min (R),
30.10 min (S).
4.21.1. (R)-3-Ethylcycloheptanone. 1H NMR (300
MHz, CDCl3): l 0.93 (t, J=7.1 Hz, 3H, CH3), 1.26–
1.50 (m, 5H), 1.55–1.65 (m, 3H), 1.86–1.95 (m, 3H),
2.47–2.52 (m, 2H). MS (EI, 70 eV) m/z: 140 (M+),
125 (M−CH3), 111 (M−C2H5). GC resolution: CP-
Cyclodextrin-B-2,3,6-M-19; oven temp.: 100°C, inj.
temp.: 200°C, det. temp.: 200°C, Flow pressure: 70
kPa; retention time: 23.43 min (S), 24.09 min (R).
4.22. General procedure for 1,4-addition to a,b-unsatu-
rated acyclic ketones
4.23.2. (2S)-1-Nitro-2-(4-methoxyphenyl)butane. 1H
NMR (300 MHz, CDCl3): l 0.83 (t, J=7.4 Hz, 3H,
CH2CH3), 1.60–1.80 (m, 2H, CH2CH3), 3.20–3.40 (m,
1H, CH), 3.79 (s, 3H, OCH3), 4.45–4.60 (m, 2H,
CH2NO2), 6.86 (d, J=8.8 Hz, 2H, Ph), 7.10 (d, J=
8.8 Hz, 2H, Ph). MS (EI, 70 eV) m/z: 209 (M+).
HPLC resolution: Chiralcel OD-H; eluent 5% IPA/n-
hexane; flow rate: 0.7 mL/min; retention time: 20.75
min (R), 32.32 min (S).
In a 25 mL round-bottomed flask was charged Cu
salt and diluted with solvent (half amount of total
solvent volume). To that solution was added ligand
(diluted with solvent) and stirred for 30 min at rt.
Et2Zn (neat) was added to the resulting solution at
0°C and stirred for 5 min. The resulting yellowish
brown solution was immersed in bath for reaction
temperature and enone (diluted in small amount of
solvent) was added at reaction temperature drop-
wisely. The reaction was monitored with TLC. After
the completion of reaction 6N HCl was added to the
reaction mixture very carefully and warmed to room
temperature. The aqueous phase was extracted with
diethyl ether and the combined organic phase was
dried with Na2SO4, filtered and evaporated. The
crude product was purified with flash column chro-
matography.
Acknowledgements
This research was supported by a Sogang University
Research Grant in 2002.
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