Highly enantioselective conjugate addition of AlMe3 to linear aliphatic enones by a designed catalyst

Article abstract of DOI:10.1002/chem.200390087

2-Hydroxy-2′-alkylthio-1,1′-binaphthy compounds are catalytic promoters of the 1,4-addition of AlMe₃ to linear aliphatic enones in THF at -40 to -48°C in the presence of [Cu(MeCN)₄]BF₄. At ligand loadings of 5-20 mol%, enantioselectivities of 80-93% are realised for most substrates. To attain these values, the use of highly pure AlMe₃ is mandatory. The presence of methylalumoxane (MAO), derived by hydrolysis, leads to reduced enantioselectivity and a conjugate addition product.

Full text of DOI:10.1002/chem.200390087

FULL PAPER
Highly Enantioselective Conjugate Addition of AlMe3 to Linear Aliphatic
Enones by a Designed Catalyst
Paul K. Fraser and Simon Woodward*[a]
Abstract: 2-Hydroxy-2'-alkylthio-1,1'-binaphthyl compounds are catalytic promot-
ers of the 1,4-addition of AlMe3 to linear aliphatic enones in THFat À40to À488C in
Keywords: alanes
catalysis ¥ cuprates ¥ S ligands ¥
thioethers
¥
asymmetric
the presence of [Cu(MeCN)4]BF4. At ligand loadings of 5 20mol%, enantioselec-
tivities of 80 93% are realised for most substrates. To attain these values, the use of
highly pure AlMe3 is mandatory. The presence of methylalumoxane (MAO), derived
by hydrolysis, leads to reduced enantioselectivity and a conjugate addition product.
formation of bimetallic catalyst structures containing alumi-
nium and copper (as in the working model in Scheme 1).[8]
The ligands 1 are easily obtained by treating monothiobi-
naphthol (MTB)[9] with appropriate alkylating agents
(Scheme 1) and their enantiopurity assayed by HPLC. Ligand
Introduction
The last five years have seen dramatic breakthroughs in what
is possible in the area of catalytic asymmetric 1,4-addition of
alkyl organometallic nucleophiles to enones. Both the prac-
tical[1] and mechanistic[2] aspects of these reactions are the
subjects of extensive reviews. Most of the successful asym-
metric versions of this chemistry have made use of diorgano
zinc reagents, especially ZnEt2, a trend started by Alexakis
(Cu catalysis) and Soai (Ni catalysis).[3] Viable ligand classes
affording >90% enantiomeric excess (ee) for the addition of
ZnR2 to cyclopentanones,[4] cyclohexanones[5] and chalcones[6]
are now available. However, relatively few publications
describing highly enantioselective addition of organometallics
to linear aliphatic enones have appeared. Very recently,
Hoveyda disclosed a modular phosphinodipetidic ligand
capable of delivering 80 95% ee in the addition of ZnR2
(R ˆ Me, Et, (CH2)nFG) to this class of enones.[7] This
publication leads us to disclose full details of our own studies
into highly selective asymmetric 1,4-addition of AlMe3 in this
arena.
1
R
a
Me
SH
OH
i) nBuLi, THF
SR
OH
b
c
d
e
f
Et
ii) RX
nPr
iPr
nBu
nC6H13
(Ra)-MTB
(Ra)-1
L
Me
Cu
S
OnBu
R
O
O
OH
AlMe2
working model....
(Ra)-2
Scheme 1. Designed ligands for asymmetric conjugate addition and a
working model (L represents a number of possible cuprate structures).
Results and Discussion
Ligand synthesis: We chose the ligands (Ra)-1a f as initial
chiral moderators in the copper-catalysed conjugate addition
of AlMe3 to nonenone 3a fashioning (‡)-(R)-4-methylnonen-
2-one (R)-4a. We have proposed that the presence of both
hard (alkoxide) and soft (thioether) donors facilitates the
1e has been reported previously;[10] it was used in the majority
of our studies and was of ꢀ95% ee. To allow us to probe the
necessity of having a group to direct the addition of the
cuprate in the transition state, the butyl ether ligand (Ra)-2
was also prepared by standard Mitsunobu chemistry with
nBuOH in the presence of triphenylphosphine (TPP) and
diethyl azodicarboxylate (DEAD) in THF.[11]
[a] Dr. S. Woodward, P. K. Fraser
School of Chemistry, The University of Nottingham
University Park, Nottingham NG7 2RD (United Kingdom)
Fax : (‡44)115-951-3564
™Magic bottle∫ effects: Our initial investigations in this area
had revealed that the ligand 1e (20mol%) promoted 1,4-
E-mail: simon.woodward@nottingham.ac.uk
776
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Chem. Eur. J. 2003, 9, No. 3

776 783
addition of AlMe3 to nonenone 3a to afford 4a in 79%
chemical yield (cy) and 71% ee in the presence of [Cu-
(MeCN)4]BF4 (Scheme 2).[10] These studies were carried out
with a solution of AlMe3 in hexane (Aldrich, 2.0m). Sub-
sequently we discovered that under these conditions (À208C,
20mol% 1e) the cy and, to a lesser extent, the ee were highly
dependent on the individual source of AlMe3 used and how it
had aged. Representative examples of the behaviour of three
commercial Aldrich sources (Bottles 1 3) are shown in
Table 1.
the formation of the double addition product 5a (n ˆ 1) as
shown by GC-MS. There were also hints in GPC chromato-
grams for these reaction mixtures of the presence of higher
O
R2
O
AlMe2
O
H
n
R1
R1
R2
O
R1
R2
10
5
n = 1, 2...
6
7
R2
R1
3/4
a
O
oligomeric products (n > 1). We reasoned that the variability
in the commercial hexane solutions of AlMe3 could be due to
variable contamination by methylalumoxane (MAO)[13] and
related hydrolysis products. A number of facts support this
hypothesis. Firstly, as all commercial bottles of AlMe3 start to
age, the ee of the derived 4a increases but its yield falls as
more 5a is formed. Finally, with highly aged commercial
AlMe3 both the ee and yield become inferior. This behaviour
can be mimicked by deliberate addition of commercial MAO
to fresh AlMe3 (Table 1). Small concentrations are beneficial
to the enantioselectivity but large excesses degrade the
catalyst performance. The MAO-induced ee improvement in
the catalytic reaction is apparently not due to kinetic
resolution of the initial aluminium enolate 6a; this is based
on the fact that the ee of 4a is not dependent on the extent of
reaction. Additionally, when isolated 4a is subjected to the
reaction conditions it is re-isolated in reduced yield but
identical ee. Deliberate addition of excess water to the initial
AlMe3 is unhelpful, but the presence of alkoxides also slightly
improves the enantioselectivity of the catalytic system.
Finally, noncommercial sources of AlMe3 in hexane (prepared
from high purity neat AlMe3) give both improved enantiose-
lectivity and yield of 4a. Neat AlMe3 is typically supplied at a
98 ‡ % purity level, the major impurities being AlMenCl3-n
(n ˆ 1, 2) and traces of MAO. Having identified the origin of
the problem, we endeavoured to find conditions that exploit-
ed this discovery.
nC5H11
nC6H13
Me
Me
Me
R1
R2
b
3
c
CH2iPr
AlMe3
cat.
d
e
f
CH2tBu Me
cat.
iPr
Me
[Cu(MeCN)4]BF4
Cy
Me
nC5H11
g
h
Et
O
nC5H11
CH2iPr
R1
R2
i
j
nC5H11
iPr
CH2iPr
(R)-4
Cy
Scheme 2. Substrates for asymmetric conjugate addition.
Table 1. Source effects in asymmetric conjugate additions of AlMe3 to
nonenone 3a, catalysed by (Ra)-1e and [Cu(MeCN)4]BF4.[a]
AlMe3
source
Additional
conditions
Conversion Yield (cy) ee
of 2 [%]
4a [%]
(R)-4a [%]
Bottle 1[b]
Bottle 2[c]
Bottle 3[d]
Bottle 3[d]
Bottle 3[d]
Bottle 3[d]
Bottle 3[d]
Bottle 3[d]
88
77
78
13
79
36
48
< 5
70
42
39
63
33
57
71
69
54
‡ 1.0equiv H2O[e]
< 5
‡ 1.0equiv EtOH[f] 7029
5 mol% MAO[g]
50mol% MAO [g]
Aged[h]
91
83
8031
81
75
73
54
MAO[g] 1.7equiv 100 mol%
Bottle 4[i]
31
79
[a] Carried out in THF at À208C, joint slow addition (20min) of AlMe 3
(1.7equiv, 1.0m in THF/hexane) and 3a (0.85m in THF) followed by further
stirring (20min); [Cu(MeCN) 4]BF4 (10mol%), 1e (20mol%). [b] Initial 2.0 m
in hexane (Aldrich) AlMe3 source; see ref. [10]. [c] Second 2.0m in hexane
(Aldrich) AlMe3 source. [d] Third 2.0m in hexane (Aldrich) AlMe3 source.
[e] Added to AlMe3 to fashion in situ ™AlMe2(OH)∫-derived hydrolysis
products. [f] Added to AlMe3 to fashion ™AlMe2(OEt)∫. [g] Commercial
MAO, 2.0m in toluene (Aldrich) remainder AlMe3 (Bottle 3). [h] Behaviour
5 months after initial opening. [i] Freshly prepared from 98% pure (Strem)
AlMe3 diluted in hexane (distilled from LiAlH4) to 2.0m.
Temperature effects and initial optimisation: We speculated
that the undesired multiple Michael addition reactions lead-
ing to 5a might be due to a high reactivity for the intermediate
aluminium enolate 6a, and that its loss might be further
promoted by extrinsic MAO presence leading to 5a. If this is
the case, using pure (AlMe3 solutions prepared ™in house∫)
and lowering the reaction temperature should improve the
stability of 6a, and hence the yield of 4a. While keeping a
fixed reaction time (20min addition of reagents followed by
20min of further stirring) the cy and ee were studied as a
function of temperature (Table 2). Encouragingly, while cy
fell (as expected), at low temperature the mass balance for the
reaction significantly improved; this indicated that degrada-
tion of 6a to 5a was minimised below À408C. As expected,
the ee value of the derived (R)-4a also rose at the lower
temperatures. An additional benefit of these conditions is that
the catalytic reaction became rather more robust with respect
to the AlMe3 source. Commercial hexane solutions, aged and
In the absence of additives, the conversion of 3a is always
high, but most commercial bottles of AlMe3 in hexane lead to
low chemical yields of 4a. Variable performance of nominally
identical bottles of commercial organometallic reagents has
been noted since the earliest days of asymmetric conjugate
additions, but is rarely explicitly cited in the literature.[12]
Efforts were made to identify the features of the ™magic
bottle∫ effect in our particular case. Firstly, GC-MS studies of
the crude reaction mixtures revealed that significant amounts
of the missing mass balance could be accounted for through
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S. Woodward and P. K. Fraser
FULL PAPER
Table 2. Temperature dependency of the ee and cy for AlMe3 (1.7equiv)
addition to 3a (10mol% [Cu(MeCN) 4]BF4, 20mol% 1e, 40min total
reaction time).[a]
attained here and compared with authentic (S)-(À)-2-meth-
ylheptan-1-ol prepared independently by Evans auxiliary
technology.[15] The latter yielded the opposite enantiomer to
that from (Ra)-1e-based catalysis, as expected. As a final
check, 3b was treated with AlMe3 by using ligand (Ra)-1e in
the expectation that it would give (‡)-4b, which is known,
through a literature correlation,[16] to correspond to R; this
also proved to be the case. Based on these facts, we have also
assigned R configurations to 4a d, f and g. For 4e and 4h j,
the rotation values do not allow confidence in the assignment
without specific degradation to known compounds.
Temperature
[8C]
Conversion
[%]
Yield (cy)
4a [%]
ee (R)-4a
[%]
À 2078
À 3071
À 4056
À 5034
47
45
4085
26
71
81
87
[a] Carried out in THF at À208C, joint slow addition (20min) of AlMe 3
(1.7equiv, 1.0m in THF/hexane) (from Aldrich >97% AlMe3) and 3a
(0.85m in THF) followed by further stirring (20min); [Cu(MeCN) 4]BF4
(10mol%), 1e (20mol%).
Optimisation at low catalyst loadings: Having attained viable
levels of enantioselectivity, we sought to overcome the need
for high ligand loadings in this system. We reasoned that at
lower catalyst loadings the reaction could be driven to
completion by use of larger excesses of terminal organo-
metallic, a trick we had previously employed in catalysis with
carbene ligands.[17] A series of runs confirmed the efficiency of
this approach (Table 4). However, exploration of variation of
the solvent or copper source led to no further improvement
(Table 5). It is readily apparent that application of conditions
that are efficacious in closely related modern systems[18] are
less helpful here. Finally, we probed the effect of ligand
structure on the outcome of the catalysis under these new
conditions (Table 6). Interestingly, under the low-temperature
pure (prepared ™in house∫ from neat AlMe3) now gave similar
results. However, the most carefully prepared pure AlMe3
solutions always gave the best ee values (typically 2 5%
higher than the commercial solutions of AlMe3 in hexane).
With these results in hand, attempts were made to optimise
the catalytic reaction at these new low temperatures.
At À40or À468C, changing the CuI/1e ratio had no effect
on the ee of 4a derived from the catalytic reaction in the range
1:1 to 1:2. In order to maximise the conversion at these low
temperatures, the copper loading was increased to 18 mol%
while keeping the loading of 1e at 20mol%. By running the
reaction for extended periods, it proved possible to enter a
synthetically useful regime with nonenone and many other
substrates (Table 3). Synthetically viable enantioselectivities
are attained except in the case where R2 is a-branched. When
either R1 or R2 is a tert-butyl group, the catalytic reaction
stops. In all cases, except 4e and 4i, the (‡)-isomer is obtained
from (Ra)-1e. We have previously assigned (‡)-4a to the (R)
stereoisomer based on the degradation of 3a to (‡)-2-
methylheptan-1-ol.[10] The optical rotations of ketones 4 and
their derived products are, however, generally rather small
and variable. For the ketones (R)-4, as the size of R2 increases
compared with R1, the size of the [a]D value first drops and
then reverses. For example, (R)-methylheptan-2-one (4; R1 ˆ
nPr, R2 ˆ Et) has [a]D24 ˆ À16.8 (c ˆ 4.26 in hexane)[14] while
(R)-4a (R1 ˆ nC5H11, R2 ˆ Me) gives [a]2D0 ˆ ‡8.7 (c ˆ 1.17 in
CHCl3, 94% ee).[7] To be absolutely sure of the correlation,
our original degradation was repeated on the high ee 4a
Table 4. Variation of excess AlMe3 in addition to 3a under 5 mol% 1e
catalysis.[a]
AlMe3 [equiv]
Conv.[b] [%]
cy[c] [%]
ee [%] (config.)
1.1
1.7
2.2
3.2
4.2
54
62
87
89
89
(
2070
27
51
41
33
‡)-R
83 (‡)-R
86 (‡)-R
82 (‡)-R
74 (‡)-R
[a] Carried out in THF at À468C, joint slow addition (20min) of AlMe 3
[2.0m in hexane prepared from Strem AlMe3 (98%)] and 3a followed by
further stirring (18 h); [Cu(MeCN)4]BF4 (5 mol%), 1e (5 mol%). [b] Con-
version based on GC. [c] GC yields versus internal standard.
Table 5. Solvent and copper-source effects in AlMe3 in addition to 3a
under 5 mol% 1e catalysis.[a]
Table 3. Asymmetric conjugate addition of AlMe3 to various enones under
Variation
Conv.[b] [%]
cy[c] [%]
ee [%] (config.)
20mol% 1e catalysis.[a]
A. Solvent
THF
THP
DME
Et2O
MeCN
toluene
B. Cu source[d]
[Cu(MeCN)4]BF4
Cu(OTf)
Enone R1
R2
Conv.[b] [%] cy 4[c] [%] ee 4 [%] (config.)
87
86
91
91
11
98
51
86
5037 (
43
< 5
50
86 (‡)-R
73 (‡)-R
‡)-R
3a
3b
3c
3d
3e
3f
3g
3 h
3i
nC5H11 Me
nC6H13 Me
CH2iPr Me
CH2tBu Me
> 96
> 96
> 96
> 96
> 97
> 96
> 96
(82)
58
63
46
55 (97)
58
52
55
62
64
85 87 (‡)-R
86 (‡)-R
87 (‡)-R
93 (‡)-R
90 93 ( À)
92 (‡)-R
80 83 ( ‡)-R
85 (‡)
42 (‡)-R
< 5
< 5
iPr
Cy
Me
Me
nC5H11 Et
87
77
73
76
51
23
33
3059 (
86 (‡)-R
39 (‡)-R
47 (‡)-R
‡)-R
nC5H11 CH2iPr > 96
nC5H11 iPr > 96
Cy CH2iPr > 96
76 (À)
Cu(OTf)2
Cu(O2CC4H3S)[e]
3j
89 (‡)
[a] Carried out in THF at À40or À468C, joint slow addition (20min) of
AlMe3 [1.7equiv; 2.0m in hexane prepared from Strem AlMe3 (>98%)]
and 3 followed by further stirring (18 h); [Cu(MeCN)4]BF4 (18 mol%), 1e
(20mol%). [b] Conversion based on GC assay. [c] Isolated, GC yields
versus internal standards in parentheses.
[a] Carried out in THF at À468C, joint slow addition (20min) of AlMe 3
[2.2equiv of 2.0m in hexane prepared from Strem AlMe3 (98%)] and 3a
followed by further stirring (18 h); [Cu(MeCN)4]BF4 (5 mol%), 1e
(5 mol%), solvent as indicated. [b] Conversion based on GC. [c] GC yields
versus internal standard. [d] All runs in THF. [e] Thiophene-2-carboxylate.
778
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Addition of AlMe3 to Enones
776 783
Table 6. Ligand effects in AlMe3 addition to 3a under 5 mol% catalysis.[a]
nitroalkenes have not been successful. In all cases only the
starting Michael acceptor has been isolated. However, we
have seen that when a,b-unsaturated esters and cyclic ethers
are present in the starting aliphatic enone these are tolerated,
and the catalyst chemospecifically adds only to the enone.
Attempted additions of AlEt3 have, thus far, led only to the
formation of conjugate addition products in lower yield and
unacceptable enantioselectivity (ee <5%). This intolerance
of AlEt3 strongly suggests that the structure of the active
catalyst incorporates an AlR3-dependent substrate binding
pocket.
Ligand (R group)
Conversion[b] [%]
cy[c] [%]
ee [%] (config.)
1a (Me)
1c (nPr)
1d (iPr)
1e (nBu)
1f (nC6H13)
2 (nBu)
87
87
63
84
8033
< 5
34
41
24
51
79 (‡)-R
84 (‡)-R
70( ‡)-R
86 (‡)-R
‡)-R
82 (
< 5
< 5
[a] Carried out in THF at À468C, joint slow addition (20min) of AlMe 3
[2.0m in hexane prepared from Strem AlMe3 (98%)] and 3a followed by
further stirring (18 h); [Cu(MeCN)4]BF4 (5 mol%), 1 or 2 (5 mol%).
[b] Conversion based on GC. [c] GC yields versus internal standard.
conditions, the favoured ligand architectures appear to
possess an n-alkyl chain of medium length in the thioether
of 1. Under the ™old∫ conditions (catalysis at À208C,
20mol% 1) all of the thioethers 1a e had delivered ꢁ70%
ee irrespective of structure. Consistent with the design model,
the presence of the thioether is mandatory; use of the closely
related ether (Ra)-2 instead gave poor catalyst performance:
both the yield and ee of the derived 4a were minimal.
Conclusion
Optimisation of the reaction conditions has led to a practical
system for the addition of AlMe3 to linear aliphatic enones by
using [Cu(MeCN)4]BF4 and binaphthol-derived thioether 1e.
Few other catalytic systems are available for this transforma-
tion that deliver these levels of stereoselectivity, and only one
other is known that employs organo aluminium reagents.[20]
The substrate selectivity profile of the [Cu(MeCN)4]BF4/1e
catalyst is unusual, and further work is required to unmask the
exact nature of the catalyst responsible.
Practicalities, limitations and mechanistic insights: The final
optimised conditions were applied to a smaller range of the
original substrates 3. Although the ee remains at the
selectivity of the 18 mol% version of the reaction, the
chemical yield is reduced. For example, 3a still delivers
enantiomeric excesses of 82 86%, but the chemical yield is
reduced to 42 48% (GC vs. internal standards). Similarly 3c
also showed a high selectivity of 83%, but reduced chemical
yield was obtained (ꢁ50% isolated). In both cases the missing
mass is shown to be present as oligomeric products (GC-MS).
The new 5 mol% catalyst system was applied to the synthesis
of (R)-muscone by addition to enone 7. Muscone was obtained
in 39% isolated yield and 77% ee. The latter figure, while
outside the synthetically useful range, is one of the highest
attained in direct catalytic approaches to this molecule.[19] To
broaden practical application of the procedure we have
investigated two methods that do not involve the use of
cryostatic cooling apparatus or syringe pumps. By using
cyclohexanone/dry ice baths it is possible to maintain a
temperature of À45(Æ5)8C for reasonable periods. Pre-
paration of the catalyst at À788C followed by sequen-
tial dropwise addition of AlMe3 and neat enone 3a, and
then further stirring at À468C for 3 hours allowed isolation
of 4a in 22% yield and 90% ee. Alternatively, if all of
the reaction components were added to [Cu(MeCN)4]BF4/1e
in THF at À788C, and the reaction mixture was allowed
to warm to room temperature over 18 hours, then 4a could
be obtained in 50 55% yield (69 79% ee) from 3a. The
results for these methods were slightly variable from run to
run due to differing rates of warming in the cold baths
employed.
Experimental Section
General: Infrared spectra were recorded by using Perkin Elmer 983G
infrared and Perkin Elmer 882 infrared spectrophotometers. Proton and
13C NMR spectra were recorded on either Jeol (JNM-GX270) or Bruker
(AM400, AV400 or DRX500) spectrometers with CHCl3 (7.27 ppm) or
tetramethylsilane (0.00 ppm) as standard; J values are given in Hz. All
spectra were recorded at ambient temperature unless otherwise noted.
Mass spectra were obtained on Finnigan-MAT1020 or Autospec VG
(electron impact ionisation, EI), Finnigan-QMS (electrospray ionisation,
ESI), VG-ZAB, or Autospec VG (fast atom bombardment, FAB).
Elemental analyses were performed by using
a Fisons Instruments
EA1108CHN elemental analyser. Optical rotations were measured on a
JASCO polarimeter model DIP-370in units of 10 À1 8cm2 gÀ1 (c in g per
100 cm3).
All reactions involving air-sensitive materials were carried out under argon
by using standard Schlenk techniques. Reaction solvents were distilled
under argon from appropriate agents immediately prior to use: THF from
either Na benzopheneone or LiAlH4, hexane from LiAlH4. Light
petroleum refers to the fraction with b.p. 40 60 8C. Solutions of AlMe3
in hexane were prepared from neat AlMe3 (neat, 98% Strem) and stored in
Schlenk storage flasks. The quality of commercial AlMe3 solutions (2.0m ,
Aldrich) was found to be batch dependent in this chemistry. The MTB
precursor to ligands 1a f is known,[9] but the following improvements were
ˆ
made to its synthesis: the BINOL was best treated with Me2NC SCl and
Me2NC CCl in two separate steps (EtOH is the best recrystallisation
ˆ
solvent for the first step; CH2Cl2/hexane for the latter). The thiophene by-
product formation (to 7-thiadibenzo[c,g]fluorine) in the Newmann Kwart
rearrangement was minimised by use of crystalline (not powdered)
precursors and prior removal of all traces of occluded solvent. Any
thiophene formed was easily removed as a first crop from EtOH. These
improvements increased the rotation of the rearranged product from ‡144
to [a]2D98 ˆ ‡159 (c ˆ 2.0in CHCl 3). The enantiopurity of ligands 1a f was
confirmed by HPLC analysis on a Daicel-AD column. The following
compounds are available by literature procedures: [Cu(MeCN)4]BF4,[21]
1e,[22] 3c,[23] 3i.[23] Isomeric 5-methylhex-4-en-2-one was removed from
commercial 3e by selective MCPBA epoxidation followed by flash
chromatography. All other compounds were used as supplied.
The substrate range of our present catalyst system also
deserves some comment. While the addition of pure AlMe3
solutions to a wide variety of aliphatic enones robustly
delivers synthetically useful ee values and chemical yields,
attempted additions to benzylideneacetone, enones bearing a
1
ˆ
conjugated vinyl function (e.g. 3: R ˆ (E)-CH CHEt), or
Chem. Eur. J. 2003, 9, No. 3
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S. Woodward and P. K. Fraser
FULL PAPER
General preparation of ligands 2a d: nBuLi (425 mL, of a 2.5m hexane
solution, 1.09 mmol) was added dropwise to a stirring solution of MTB[9]
(0.30 g, 0.99 mmol) in THF at 08C under an inert atmosphere. Neat alkyl
halide (1.09 mmol) was added, the solution was allowed to warm to room
temperature and monitored by TLC (dichloromethane/light petroleum
1:1). When the reaction was complete (1 h 1 d), the reaction mixture was
quenched with HCl (2m, 5 mL) and extracted with dichloromethane,
washed with brine and dried over MgSO4. Purification by flash column
chromatography (dichloromethane/light petroleum 1:1) yielded low-melt-
ing-point solids or oils whose spectroscopic properties were consistent with
the desired formulation.
J ˆ 8.2 plus small unresolved long-range couplings, 1H; H8or8'), 7.22 (ddd,
J ˆ 8.2, 6.8, 1.3, 1H; H6,7,6'or7'), 7.28 (ddd, J ˆ 8.3, 6.8, 1.3, 1H; H6,7,6'or7'), 7.31
(ddd, J ˆ 8.2, 6.8, 1.3, 1H; H6,7,6'or7'), 7.35 (d, J ˆ 8.9, 1H; H3or3'), 7.44 (ddd,
J ˆ 8.2, 6.8, 1.2, 1H; H6,7,6'or7'), 7.70(d, J ˆ 8.8, 1H; H3or3'), 7.87 (d, J ˆ 8.2,
plus small unresolved long-range couplings, 1H; H5or5'), 7.90(d, J ˆ 8.2, plus
small unresolved long-range couplings, 1H; H5or5'), 7.94 (d, J ˆ 8.9, 1H;
H4or4'), 7.98 (d, J ˆ 8.8, 1H; H4or4'); 13C NMR (125.8 MHz, CDCl3) d ˆ 22.9
(CHMe2a), 23.3 (CHMe2b), 36.4, 117.3, 117.6, 123.5, 124.6, 125.4, 126.0,
126.3, 126.7, 127.5, 128.3 (2C), 129.2, 129.6, 129.8, 130.3, 132.0, 133.5, 133.7,
137.5, 150.7; IR (KBr disc): nÄmax ˆ 3510(w, br, OH), 3429 (w, br, OH), 2960
À
À
À
(w, C H), 2903 (s, C H), 2863 (C H), 1618 (m), 1598 (m), 1205 (m), 1144
‡
(m), 813 (m), 747 cmÀ1 (m); FAB: m/z (%): 344 (20) [M ], 307 (30), 154
(Ra)-(À)-S-Methyl-2-hydroxy-2'-mercapto-1,1'-binaphthyl (1a): Yield
60%; low-melting-point solid; [a]2D4 ˆ À26.5 (c ˆ 1.02 in CHCl3); 1H NMR
(400.1 MHz, CDCl3) d ˆ 2.44 (s, 3H; Me), 4.81 (brs, 1H; OH), 6.97 (d, J ˆ
8.3 plus small unresolved long-range couplings, 1H; H8or8'), 7.08 (d, J ˆ 8.3
plus small unresolved long-range couplings, 1H; H8or8'), 7.26 (ddd, J ˆ 8.3,
6.8, 1.3, 1H; H6,7,6'or7'), 7.30(ddd, J ˆ 8.3, 6.8, 1.3, 1H; H6,7,6'or7'), 7.34 (ddd, J ˆ
8.2, 6.8, 1.3, 1H; H6,7,6'or7'), 7.37 (d, J ˆ 8.8, 1H; H3or3'), 7.45 (ddd, J ˆ 8.1, 6.8,
1.3, 1H; H6,7,6'or7'), 7.60(d, J ˆ 8.8, 1H; H3or3'), 7.89 (d, J ˆ 8.1, plus small
unresolved long-range couplings, 1H; H5or5'), 7.92 (d, J ˆ 8.2, plus small
unresolved long-range couplings, 1H; H5or5'), 7.96 (d, J ˆ 8.8, 1H; H4or4'),
8.04 (d, J ˆ 8.8, 1H; H4or4'); 13C NMR (67.8 MHz, CDCl3) d ˆ 15.6 (Me),
116.7, 117.8, 123.0, 123.9, 124.6, 125.1, 125.8 (3C), 127.1, 127.8, 128.5, 129.5,
130.1, 130.8, 131.7, 133.4, 133.6, 139.1, 151.2; IR (KBr disc): nÄmax ˆ 3530(m,
br, OH), 3425 (m, br, OH), 1618 (m), 1595 (m), 1206 (m), 1140 (m),
‡
(100); found (HRMS, FAB) ˆ 344.1231 [M ], C23H20OS requires
M
344.1235.
(Ra)-(À)-S-Hexyl-2-hydroxy-2'-mercapto-1,1'-binaphthyl (1 f): Yield 52%;
low-melting-point solid; [a]2D4 ˆ À9.9 (c ˆ 1.19 in CHCl3); 1H NMR
(500.1 MHz, CDCl3) d ˆ 0.88 (t, J ˆ 7.1, 3H; (CH2)3Me), 1.25 1.38 (m,
6H; (CH2)3Me), 1.59 (distorted quintet, J ˆꢁ 6.0, 2H; SCH2CH2), 2.92 (m,
2H; SCH2), 4.83 (brs, 1H; OH), 7.00 (d, J ˆ 8.3 plus small unresolved long-
range couplings, 1H; H8or8'), 7.18 (d, J ˆ 8.2 plus small unresolved long-
range couplings, 1H; H8or8'), 7.27 (ddd, J ˆ 8.2, 6.8, 1.3, 1H; H6,7,6'or7'), 7.32
(ddd, J ˆ 8.3, 6.8, 1.3, 1H; H6,7,6'or7'), 7.36 (ddd, J ˆ 8.2, 6.8, 1.3, 1H; H6,7,6'or7'),
7.39 (d, J ˆ 8.9, 1H; H3or3'), 7.48 (ddd, J ˆ 8.2, 6.8, 1.2, 1H; H6,7,6'or7'), 7.62 (d,
J ˆ 8.8, 1H; H3or3'), 7.91 (d, J ˆ 8.2, plus small unresolved long-range
couplings, 1H; H5or5'), 7.94 (d, J ˆ 8.2, plus small unresolved long-range
couplings, 1H; H5or5'), 7.97 (d, J ˆ 8.9, 1H; H4or4'), 8.00 (d, J ˆ 8.8, 1H;
H4or4'); 13C NMR (100.6 MHz, CDCl3) 14.2 (Me), 22.7 (CH2), 28.7 (CH2),
29.3 (CH2), 31.5 (CH2), 32.5 (CH2), 117.1, 117.8, 123.7, 124.6, 124.7, 125.3,
125.9, 126.9, 127.6, 128.4 (2C), 128.5, 129.3, 129.8, 130.5, 131.9, 133.5, 133.7,
‡
812cmÀ1 (s); ES: m/z (%): 317 (100) [M ‡H]; found (HRMS, ES) ˆ
‡
317.0997 [M ‡H], C21H17OS requires M 317.1000. This compound has
been reported, but no spectroscopic details have appeared to our know-
ledge.[24]
À
138.1, 151.0; IR (KBr disc): nÄmax ˆ 3548 (w, OH), 2945 (w, C H), 2926 (w,
(Ra)-(À)-S-Ethyl-2-hydroxy-2'-mercapto-1,1'-binaphthyl (1b): Yield 62%;
low-melting-point solid; [a]2D4 ˆ À19.5 (c ˆ 1.06 in CHCl3); 1H NMR
(400.1 MHz, CDCl3) d ˆ 1.21 (t, J ˆ 7.1, 3 H ; CH2Me), 2.88 (m, 2H;
CH2Me), 4.81 (brs, 1H; OH), 6.95 (d, J ˆ 8.2 plus small unresolved long-
range couplings, 1H; H8or8'), 7.13 (d, J ˆ 8.2 plus small unresolved long-
range couplings, 1H; H8or8'), 7.21 (ddd, J ˆ 8.2, 6.8, 1.3, 1H; H6,7,6'or7'), 7.25
(ddd, J ˆ 8.2, 6.8, 1.3, 1H; H6,7,6'or7'), 7.30(ddd, J ˆ 8.0, 6.8, 1.3, 1H; H6,7,6'or7'),
7.34 (d, J ˆ 8.8, 1H; H3or3'), 7.41 (ddd, J ˆ 8.1, 6.8, 1.3, 1H; H6,7,6'or7'), 7.59 (d,
J ˆ 8.8, 1H; H3or3'), 7.85 (d, J ˆ 8.1, plus small unresolved long-range
couplings, 1H; H5or5'), 7.86 (d, J ˆ 8.2, plus small unresolved long-range
couplings, 1H; H5or5'), 7.91 (d, J ˆ 8.8, 1H; H4or4'), 7.94 (d, J ˆ 8.8, 1H;
H4or4'); 13C NMR (67.8 MHz, CDCl3) d ˆ 14.1 (Me), 26.2 (CH2), 116.8, 117.6,
123.5, 124.2, 124.4, 125.0, 125.6, 126.7, 127.4, 128.2 (3C), 129.1, 129.6, 130.3,
À
À
C H), 2856 (w, C H), 1622 (m), 1582 (m), 1507 (m), 1432 (m), 1338 (m),
1267 (m), 1251 (m), 967 (s), 820(s), 810(s), 746 cm À1 (s); ES: m/z (%): 387
(100) [M ], found (HRMS) ˆ 386.1699 [M ], C23H20OS requires
‡
‡
M
386.1704.
(Ra)-(À)-O-Butyl-2-hydroxy-2'-hydroxy-1,1'-binaphthyl (2): Triphenyl-
phosphine (0.734 g, 2.80 mmol) in dry THF (25 mL) and diethyl azodicar-
boxylate (DEAD) (0.44 mL, 2.80 mmol) were added to a stirring solution
of (Ra)-BINOL (0.80 g, 2.80 mmol) and nBuOH (1.28 mL 13.97 mmol).
Yield 70%; low-melting-point solid (when synthesised, we found genuine
(Æ)-2 to be a white solid of m.p. 94 958C); [a]2D4 ˆ ‡7.6 (c ˆ 1.2 in CHCl3,
1
>98% ee); H NMR (400.1 MHz, CDCl3); 0.76 (t, J ˆ 7.3, 3H; Me), 1.14
(sextet, J ˆ 7.3, 2H; MeCH2), 1.52 (quintet, J ˆ 6.8, 2H; CH2Et), 4.04 (m,
3H; ArOCH2nPr), 5.23 (brs, 1H; OH), 7.19 (d, J ˆ 8.3, 1H; H8or8'), 7.27
7.45 (m, 7H, Ar), 7.92-7.96 (m, 2H; H5and5'), 7.97 (d, J ˆ 8.8, 1H; H4or4'), 8.02
(d, J ˆ 9.0, 1H; H4or4'); 13C NMR (100.6 MHz, CDCl3) d ˆ 13.6 (Me), 18.8
(CH2), 31.3 (CH2), 69.5 (CH2), 115.4, 115.7, 116.5, 117.6, 123.2, 124.2, 125.1,
125.2, 126.3, 127.2, 128.1, 128.2, 129.2, 129.6, 129.7, 130.8, 134.0, 134.2, 151.4,
155.6; IR (diffuse reflectance): nÄmax ˆ 3472 (m, OH), 3417 (w, OH), 2969 (w,
À
131.6, 133.2, 133.5, 137.6, 150.8; IR (KBr disc): nÄmax ˆ 3501 (w, C H), 3500
À
À
(s, br, OH), 3417 (m, br, OH), 2961 (w, C H), 2924 (w, C H), 2862 (w,
À
C H), 1618 (s), 1595 (s), 1501 (s), 1203 (s), 1143 (s), 969 (m), 814 (s),
747 cmÀ1 (m); ES m/z (%): 331 (100) [M ‡H]; found (HRMS, FAB) ˆ
‡
‡
330.1065 [M ]; C22H18OS requires M 330.1078. This compound has been
reported, but no spectroscopic details have appeared to our knowledge.[24]
À
À
C H), 2957 (w, C H), 1619 (m), 1590(m), 1505 (m), 1379 (m), 1272 (m),
1205 (m), 1179 (m), 1081 (m, C-O), 814 cmÀ1 (s). Racemic 2 has appeared,
but apparently no spectroscopic details have been published.[25]
(Ra)-(À)-S-Propyl-2-hydroxy-2'-mercapto-1,1'-binaphthyl (1c): Yield
72%; colourless oil; [a]2D4 ˆ À8.6 (c ˆ 3.42 in CHCl3); 1H NMR
(400.1 MHz, CDCl3) d ˆ 0.90 (t, J ˆ 7.4, 3H; Me), 1.59 (sextet, J ˆ 7.4,
2H; central CH2), 2.86 (m, 2H; SCH2), 4.78 (brs, 1H; OH), 6.96 (d, J ˆ 8.2
plus small unresolved long-range couplings, 1H; H8or8'), 7.13 (d, J ˆ 8.2 plus
small unresolved long-range couplings, 1H; H8or8'), 7.22 (ddd, J ˆ 8.2, 6.8,
1.3, 1H; H6,7,6'or7'), 7.28 (ddd, J ˆ 8.2, 6.8, 1.3, 1H; H6,7,6'or7'), 7.32 (ddd, J ˆ 8.0,
6.8, 1.3, 1H; H6,7,6'or7'), 7.35 (d, J ˆ 8.8, 1H; H3or3'), 7.43 (ddd, J ˆ 8.1, 6.8, 1.3,
1H; H6,7,6'or7'), 7.64 (d, J ˆ 8.8, 1H; H3or3'), 7.87 (d, J ˆ 8.1, plus small
unresolved long-range couplings, 1H; H5or5'), 7.89 (d, J ˆ 8.2, plus small
unresolved long-range couplings, 1H; H5or5'), 7.93 (d, J ˆ 8.8, H4or4'), 7.98
(1H; d, J ˆ 8.8, 1H; H4or4'); 13C NMR (67.8 MHz, CDCl3) d ˆ 13.4 (Me),
22.5 (CH2), 34.2 (CH2), 117.6, 123.4, 124.4 (2C), 125.0, 125.7, 126.7, 127.4,
128.1, 128.2 (3C), 128.4, 129.1, 129.6, 130.3, 131.7, 133.3, 137.8, 150.8; IR
Enone preparation by LDA-enolate chemistry: Diisopropylamine
(3.34 mL, 23.8 mmol) in THF (30mL) was cooled to À788C, and nBuLi
(12.0mL, 2.0 m, 23.8 mmol) was added. The solution was stirred for 30min
before addition of ketone (23.8 mmol) in THF (0.7 mL). After 30 min, neat
aldehyde (23.8 mmol) was added dropwise. The solution was stirred for a
further 30min at À788C before the cooling bath was removed, and stirring
was continued at ambient temperature for 10mins. Water (20mL) was
added, and the layers were separated, the organic phase was dried
(MgSO4), and the solvent was removed. The residue was dissolved in
diethyl ether, conc. HCl (ca 5 mL) was added, and the elimination of the
alcohol was monitored by TLC. Flash column chromatography (diethyl
ether/pentane 1:8) or Kugelrohr distillation followed. Typically 55 70%
isolated yield was obtained.
À
À
(CHCl3 solution): nÄmax ˆ 3537 (s, OH), 2966 (s, C H), 2933 (m, C H), 2874
À
(w, C H), 1621 (s), 1596 (s), 1466 (m), 1381 (s), 1355 (s), 1145 (s), 1120(m),
À1
‡
970(m), 862 cm (w); ES: m/z (%): 345 (100) [M ‡H]; found (HRMS,
Enone preparation by Wittig chemistry: The aldehyde (20.7 mmol) and
Ph3P CH(COMe) (21.7 mmol) were heated to reflux in THF (40mL) for
‡
FAB) ˆ 344.1231 [M ], C23H20OS requires M 344.1235.
ˆ
(Ra)-(À)-S-(1-methyl)ethyl-2-hydroxy-2'-mercapto-1,1'-binaphthyl (1d):
Yield 35%; low-melting-point solid; [a]2D4 ˆ À4.1 (c ˆ 1.06 in CHCl3);
1H NMR (400 MHz, CDCl3) d ˆ 1.19 (d, J ˆ 6.7, 3H; CHMe2a), 1.25 (d, J ˆ
6.7, 3H; CHMe2b), 3.53 (septet, J ˆ 6.7, 1H; SCH), 4.76 (brs, 1H; OH), 6.95
(d, J ˆ 8.2 plus small unresolved long-range couplings, 1H; H8or8'), 7.13 (d,
6 h overnight, the solution was cooled, and the solvent was removed. The
enone was extracted from the white precipitate with pentane (5 Â 10mL),
and the pentane was removed under reduced pressure. The resulting oil was
purified by column chromatography (hexane/Et2O 23:2). Typically 55
75% isolated yield was obtained.
780
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0903-0780 $ 20.00+.50/0
Chem. Eur. J. 2003, 9, No. 3

Addition of AlMe3 to Enones
776 783
(E)-6,6-Dimethylhept-3-en-2-one (3d): Yield 50%; oil; 1H NMR
(400.1 MHz, CDCl3) d ˆ 0.94 (s, 9H; tBu), 2.11 (dd, J ˆ 7.8, 1.3, 2H;
nonenone (83 mL, 0.50 mmol), and the mixture was allowed to warm slowly
to room temperature overnight. (Alternatively a cyclohexenone/CO2 bath
may be used to maintain approximately À508C reaction temperature).
The conjugate addition products were isolated directly from the catalytic
reactions by flash chromatography. Compound (R)-(‡)-4a had literature
properties.[7, 10] We obtained [a]D20 ˆ ‡6.8 (c ˆ 1.17 in CHCl3 for 83% ee
material). Details of the enantiomer separations are given in Table 7.
ˆ
CH2), 2.25 (s, 3H; MeCO), 6.06 (dt, J ˆ 15.8, 1.3 1H; CHCO), 6.82 (dt,
15.8, 7.8, 1H; CH2CH ); 13C NMR (125.8 MHz, CDCl3) d ˆ 27.4, 29.8
ˆ
ˆ
ˆ
ˆ
(tBu), 31.9, 47.3 (Me), 133.7 ( CH), 146.2 ( CH), 198.9 (C O); IR (liquid
À
À
ˆ
film): nÄmax ˆ 2958 (s, C H) 2868 (m, C H), 1698 (m), 1676 (s, C O), 1628
(m), 1474 (m), 1431 (w), 1394 (w), 1365 (s), 1261 (m), 1251 (m), 1236 (m),
‡
1185 (w), 982 cmÀ1 (m); found (HRMS, EI) ˆ 140.11976 [M ], C9H16O
requires M 140.12012. Only limited literature data are available for this
compound.[26]
Table 7. Chiral GC conditions for the analysis of addition products 4.[a]
(E)-4-Cyclohexylbut-3-en-2-one (3 f): Oil; 1H NMR (400.1 MHz, CDCl3)
d ˆ 1.10 1.38 (m, 5H; Cy), 1.68 1.80 (m, 5H; Cy), 2.15 (m, 1H;
Product
Column
Programme
Elution order [min]
(config.)[b]
ˆ
ˆ
(CH2)2CHCH ), 2.25 (s, 3H; Me), 6.05 (dd, J ˆ 16.1, 1.3, 1H; CHCO),
6.74 (dd, 16.1, 6.8, 1H; CyCH ); 13C NMR (100.6 MHz, CDCl3) d ˆ 26.1
4a
4b
4c
4d
4e
4 f
4g
4 h
4i
6-Me-2,3-pe-d-CD
6-Me-2,3-pe-d-CD
6-Me-2,3-pe-d-CD
6-Me-2,3-pe-d-CD
6-Me-2,3-pe-d-CD
2,6-Me-3-pe-d-CD
6-Me-2,3-pe-d-CD
2,6-Me-3-pe-d-CD
2,6-Me-3-pe-d-CD
2,6-Me-3-pe-d-CD
708C isothermal
708C isothermal
758C isothermal
658C isothermal
708C isothermal
1208C isothermal
758C isothermal
958C isothermal
958C isothermal
1158C isothermal
21.77 (À)-(S)
22.40( ‡)-(R)
39.39 (À)-(S)
41.35 (‡)-(R)
6.36 (À)-(S)
ˆ
ˆ
ˆ
(Cy), 26.2 (Cy), 27.2, 32.1, 41.0(Me), 129.2 ( CH), 153.7 ( CH), 199.5
ˆ
À
À
(C O) ; IR (liquid film): nÄmax ˆ 2925 (s, C H), 2852 (s, C H), 1697 (s,
À1
ˆ
ˆ
ˆ
C O), 1675 (s, C C), 1624 (s, C C), 1449 (m), 1357 (m), 1252 (s), 909 cm
‡
(s); found (HRMS, EI) ˆ 152.12058 [M ], C10H16O requires M 152.12012.
These data are comparable to those for 3 f prepared by a different route.[27]
6.47 (‡)-(R)
13.53 (À)-(S)
14.05 (‡)-(R)
6.10( ‡/ À )[c]
6.40( ‡/ À )
(E)-4-Dec-4-en-3-one (3g): Oil; 1H NMR (500.1 MHz, CDCl3) d ˆ 0.90 (t,
J ˆ 6.8, 3H; (CH2)4Me), 1.10(t, J ˆ 7.3, 3H; COCH2Me), 1.28 1.38 [m, 4H;
ˆ
(CH2)2Me], 1.47 (quin, J ˆ 7.3, 2H; CHCH2CH2), 2.12 (dq, J ˆ 1.3, 7.3,
ˆ
2H; CH2CH ), 2.57 (q, J ˆ 7.3, 2H; COCH2Me), 6.10(dt, J ˆ 16.0, 1.3, 1H;
31.81 (À)-(S)
34.40( ‡)-(R)
29.56 (À)-(S)
31.10( ‡)-(R)
41.07 (‡/ À )[c]
44.83 (‡/ À )
22.57 (‡/ À )[c]
24.90( ‡/ À )
14.53 (À/ ‡ )[c]
17.00 (À/ ‡ )
CHCO), 6.84 (dt, J ˆ 16.0, 6.9, 1H; CH2CH ); 13C NMR (125.8 MHz,
ˆ
ˆ
ˆ
CDCl3) d ˆ 8.2 (Me), 14.0(Me), 22.5, 27.9, 31.4, 32.5, 33.2, 130.1 ( CH),
ˆ
ˆ
À
147.3 ( CH), 201.3 (C O); IR (liquid film): nÄmax ˆ 2958 (s, C H), 2931 (s,
À
À
ˆ
ˆ
C H), 2858 (s, C H), 1700 (m), 1676 (s, C O), 1631 (s, C C), 1459 (m),
1357 (m), 1202 (m), 983 cmÀ1 (m); found (HRMS, EI) ˆ 154.136073 [M ],
‡
C10H18O requires M 154.135765. This compound has appeared, but no data
were presented.[28]
(E)-2-Methylundec-5-en-4-one (3 h): Oil; 1H NMR (400.1 MHz, CDCl3)
d ˆ 0.89 (t, J ˆ 7.0, 3H; (CH2)4Me), 0.93 (d, J ˆ 6.7, 6H; CHMe2), 1.27 1.34
4j
ˆ
(m, 4H; (CH2)2Me), 1.46 (quintet, J ˆ 7.0, 2 H ; C H2CH2CH ), 2.16 (m, 1H;
[a] Carried out on equipment described previously:[10] 6-Me-2,3-pe-d-CD is
25 m Octakis(6-0-methyl-2,3-di-O-pentyl-g-cyclodextrin 0.25 mm internal
diameter (60% in OV1701, w/w)); 2,6-Me-3-pe- d-CD is 25 m Octakis(2,6-
di-O-methyl-3 0-pentyl)-g-cyclodextrin 0.25 mm i.d. (50% in OV1701
w/w.[23] [b] Antipode assignment based on largest peak in GC trace
corresponding with the sign of the optical rotation of the bulk sample.
[c] Value of optical rotation does not allow for confident assignment.
ˆ
CH2CHMe2) overlapped by 2.21 (dq, J ˆ 1.5, 7.0, 2H; CH2CH ), 2.40(d,
ˆ
J ˆ 7.0, 2H; COCH2), 6.08 (dt, J ˆ 15.9, 1.5, 1H; CHCO), 6.81 (1H; dt, J ˆ
15.8, 7.0, CH2CH ); 13C NMR (100.6 MHz, CDCl3) 14.3 (Me), 22.8, 23.0
ˆ
ˆ
ˆ
(CHMe2), 25.5, 28.1, 31.7, 32.8, 49.5, 131.1 ( CH), 147.8 ( CH), 201.0
ˆ
À
À
(C O); IR (liquid film): nÄmax ˆ 2965 (s, C H), 2930(m, C H), 2871 (m,
C H), 1676 (s, C O), 1626 (C C), 1360(s), 1259 (s), 983 cm À1 (m); found
À
ˆ
ˆ
‡
(HRMS, EI) ˆ 182.16706 [M ], C12H22O requires M 182.16707.
(E)-1-Cyclohexyl-5-methyl-hex-1-en-3-one
(3j):
Oil;
1H
NMR
(R)-(‡)-4-methyldecan-2-one (4b): Isolated yield 58%; oil; [a]2D4 ˆ ‡9.6
(c ˆ 0.98 in CHCl3, 86% ee); 1H NMR (400.1 MHz, CDCl3) d ˆ 0.89 (t, J ˆ
6.9, 3H; (CH2)5Me), overlapped by 0.89 (d, J ˆ 6.6, 3H; MeCH), 1.1 1.35
(m, 10H; (CH2)5), 1.89 (m, 1H; nHexCHMe), 2.13 (s, 3H; MeCO), 2.22
(400.1 MHz, CDCl3) d ˆ 0.93 (d, J ˆ 6.7, 6H; CHMe2), 1.08 1.37 (m, 5H;
Cy), 1.64 1.80(2m, 5H; Cy) 2.14 (tsept, J ˆ 7.0, 6.6, 2H; CHMe2) 2.27 (m,
ˆ
1H; CHCH ), 2.40(d, J ˆ 7.0, 2 H ; CH2iPr) 6.04 (dd, 16.0, 1.2, 1H;
CHCO), 6.74 (dd, J ˆ 16.0, 6.8, 1H; CHCH ); 13C NMR (100.6 MHz,
ˆ
ˆ
ˆ
ˆ
CDCl3); 22.9, 25.3, 25.9, 26.1, 32.0, 40.8, 49.3, 128.4 ( CH), 152.4 ( CH),
(dd, J ˆ 15.8, 8.1, 1H; CH2aCOMe), 2.40(dd,
J ˆ 15.8, 5.7, 1H;
ˆ
À
À
CH2bCOMe); 13C NMR (100.6 MHz, CDCl3) d ˆ 14.5, 20.2, 23.0, 27.3,
201.2 (C O); IR (liquid film): nÄmax ˆ 2927 (s, br, C H), 2853 (s, C H), 1695
ˆ
ˆ
ˆ
(s, C O), 1676 (s, C O), 1626 (s, C C), 1465 (m), 1449 (m), 1366 (m), 1293
ˆ
29.7, 29.8, 30.8, 32.3, 37.3, 51.7, 209.6 (C O); IR (liquid film): nÄmax ˆ 2956 (s,
(m), 1196 (m), 981 cmÀ1 (m); found (HRMS, EI) ˆ 194.16679 [M ],
‡
À
À
À
À
ˆ
C H), 2926 (s, C H), 2872 (s, C H), 2855 (s, C H), 1717 (s, C C), 1463
(m), 1364 (m), 1165 cmÀ1 (m); found (HRMS, EI) ˆ 170.16747 [M ],
‡
C13H22O requires M 194.16707.
C11H22O requires M 170.16707. Apparently only polarimetry data have
been published for (R)-4b.[16]
General procedure for asymmetric conjugate additions: All conjugate
addition preparations were carried out in flame-dried argon-filled glass-
ware.
(R)-(‡)-4,6-Dimethylheptan-2-one (4c): Isolated yield 63%; oil; [a]D24
ˆ
1
‡14.4 (c ˆ 1.17 in CDCl3, 87% ee); H NMR (400.1 MHz, CDCl3); 0.87
0.89 (3  d, J ˆꢁ 6.6, 9H; diastereotopic CHMe2 overlapped by CHMe),
1.02 1.13 (m, 2H; iPrCH2CH), 1.62 (apparent dbrnonet, J ˆ 1.1, 6.6, 1H;
CH2CHMe2), 2.07 (m, 1H; MeCH), 2.13 (s, 3H; COMe), 2.21 (dd, J ˆ 15.6,
8.2, 1H; CH2aCOMe), 2.38 (dd, J ˆ 15.7, 5.5, 1H; CH2bCOMe); 13C NMR
(100.6 MHz, CDCl3) d ˆ 20.2 (Me), 22.5 (Me), 23.6, 25.6, 27.4, 29.1, 46.9,
Cryostat method: A solution of ligand (35.9 mg, 0.10 mmol, 20 mol%) in
THF (1 mL) was added to [Cu(MeCN)4]BF4 (28.3 mg, 0.09 mmol,
18 mol%) and cooled by cryostat (À458C to À468C). The enone
(0.50 mmol) was diluted with THF (0.5 mL). AlMe3 (1.7 eqiuv, ꢁ2.0m,
0.85 mmol) was diluted to 0.8 mL with THF. An aliquot of the AlMe3
(0.1 mL) solution was added to the ligand copper solution to form the
precatalyst, and the solution was stirred for about 1 min. The remaining
reagents were added simultaneously by syringe pump over 20mins. The
solution was stirred for a further 18 h. Undecane (50 mL) was added as
internal standard. HCl (2m, 2 mL) was added to quench the reaction, and
the solution was warmed to room temperature with rapid stirring.
ˆ
À
À
52.0, 228.2 (C O); IR (liquid film): nÄmax ˆ 2956 (s, C H), 2930(s, C H),
À
ˆ
2871 (s, C H), 2842 (w), 1717 (s, C C), 1468 (m), 1421 (w), 1384 (m), 1365
(s), 1169 cmÀ1 (m); found (HRMS, EI) ˆ 142.13560[ M ], C9H18O requires
‡
M 142.13577. Only limited data have appeared for this compound.[29]
(R)-(‡)-4,6,6-Trimethylheptan-2-one (4d): Isolated yield 46%; oil; [a]D24
ˆ
Non-cryostat methods:
A
solution of ligand (35.9 mg, 0.10 mmol,
‡6.7 (c ˆ 0.99 in CHCl3, 93% ee); 1H NMR (400.1 MHz, CDCl3) d ˆ 0.91
(s, 9H; tBu), 0.94 (d, J ˆ 6.6, 3H; tBuCHMe), 1.11 (dd, J ˆ 13.9, 6.3, 1H;
CH2atBu), 1.19 (dd, J ˆ 13.9, 4.2, 1H; CH2btBu), 2.04 2.14 (m, 1H; CHMe)
overlapped by 2.12 (s, 3H; COMe), 2.27 (dd, J ˆ 15.8, 8.2, 1H; CH2a
COMe), 2.42 (dd, J ˆ 15.8, 5.5, 1H; CH2bCOMe); 13C NMR (100.6 MHz,
20mol%) in THF (1 mL) was added to [Cu(MeCN) 4]BF4 (28.3 mg,
0.09 mmol, 18 mol%), and the resulting mixture was cooled to À208C.
An aliquot (0.02 mL) of a solution of AlMe3 (2.2 eqiuv, 0.58 mL, 1.91m,
1.10mmol in hexanes) was added, forming the precatalyst, and the solution
was cooled to À788C. The remaining AlMe3 was added, followed by neat
ˆ
CDCl3) d ˆ 23.1, 26.3, 30.4 (3C, tBu), 30.8, 31.5 (C), 51.3, 53.9, 209.4 (C O);
Chem. Eur. J. 2003, 9, No. 3
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0903-0781 $ 20.00+.50/0
781

S. Woodward and P. K. Fraser
FULL PAPER
À1
À
À
ˆ
À
ˆ
IR (liquid film): nÄmax ˆ 2955 (s, C H), 2870(m, C H), 1717 (s, C C), 1364
C H), 1711(s, C C), 1448 (m), 1366 cm (m); found (HRMS, EI) ˆ
‡
‡
(s), 1246 (w), 1157 cmÀ1 (m); found (HRMS, EI) ˆ 165.15113 [M ],
198.197378 [M ], C13H26O requires M 198.198366.
C10H20O requires M 165.15141. Only limited data have appeared for this
(À)-(R)-Muscone: Addition of AlMe3 to enone 7 under standard 5%
loading conditions afforded Muscone after flash chromatography (eluent:
2% Et2O in petrol). Yield 39%; oil; [a]2D0 ˆ À7.6 (c ˆ 1.05 in CDCl3, 77%
compound.[30]
(À)-4,5-Dimethylhexan-2-one (4e): Isolated yield 55%, 97% conversion
(GC); oil; [a]2D4 ˆ À6.6 (c ˆ 1.05 in CDCl3, 90 %ee); 1H NMR (400.1 MHz,
CDCl3) d ˆ 0.83 (d, J ˆ 6.8, 3H; CHMe2a), 0.84 (d, J ˆ 6.8, 3H; CHMe2b),
0.85 (d, J ˆ 6.8, 3H; iPrCHMe), 1.50(dbrseptet, J ˆ 6.8, 2.1, 1H; CHMe2),
1.93 (m, 1H; CHMe), 2.14 (s, 3H; COMe), 2.20(dd, J ˆ 15.7, 9.2, 1H;
CH2aCOMe), 2.44 (dd, J ˆ 15.7, 4.7, 1H; CH2bCOMe); 13C NMR
(67.8 MHz, CDCl3) d ˆ 15.9 (Me), 18.3 (Me), 19.8 (Me), 30.4, 32.2, 34.7,
1
ee); H NMR (400.1 MHz, CDCl3) d ˆ 0.94 (d, J ˆ 6.7, 3H; CHMe), 1.20
1.38 (m, 20H; (CH2)10), 1.53 1.75 (m, 2H; (CH2)10CH2CHMe), 2.06 (m,
1H; CHMe), 2.19 (dd, J ˆ 14.9, 5.0, 1H; CHCH2aCO), 2.41 (t, J ˆ 6.9, 2H;
(CH2)10CH2CO) overlapped by 2.43 (dd, J ˆ 14.9, 8.2, 1H; CHCH2bCO);
13C NMR (100.6 MHz, CDCl3) d ˆ 21.3 (Me), 23.2, 25.2, 26.3, 26.4, 26.7,
ˆ
26.7, 26.8, 26.9, 27.3, 27.7, 29.2, 35.7, 42.2, 50.6, 212.3 (C O); IR (liquid film):
À1
À
À
ˆ
nÄmax ˆ 2928 (s, C H), 2857 (s, C H), 1711 (s, C C), 1459 cm (m); found
ˆ
À
À
48.4, 209.0 (C O); IR (liquid film): nÄmax ˆ 2959 (s, C H), 2875 (s, C H),
‡
À1
(HRMS, EI) ˆ 238.22977 [M ], C16H30O requires M 238.22966. These data
ˆ
1717 (s, C C), 1464 (m), 1368 (m), 1164 cm (m); found (HRMS, EI) ˆ
were consistent with published values.[31]
‡
128.12047 [M ], C8H16O requires M 128.12012.
(R)-(‡)-4-Cyclohexyl-4-methylbutan-2-one (4 f): Isolated yield 58%; oil;
[a]2D4 ˆ ‡5.4 (c ˆ 1.03 in CHCl3, 92% ee); 1H NMR (400.1 MHz, CDCl3)
d ˆ 0.85 (d, J ˆ 6.8, 3H; CyCHMe), 0.94 1.50 (m, 2H; Cy) overlapped by
1.30 1.50(m, 4H; Cy), 1.60 1.70(m, 3H; Cy), 1.70 1.79 (m, 2H; Cy), 1.90
(m, 1H; CyCH), 2.13 (s, 3H; MeCO), 2.20(dd, J ˆ 15.8, 9.2, 1H;
CH2aCOCy), 2.47 (dd, J ˆ 15.8, 4.7, 1H; CH2bCOCy); 13C NMR
(100.6 MHz, CDCl3) d ˆ 17.0, 27.0, 27.1, 29.5, 30.7, 34.6, 43.2, 49.0, 209.9
Acknowledgement
We thank the EPSRC for their support under grants GR/M84909 and GR/
N37339; for access to their Mass Spectrometry Service (Swansea); and for a
studentship (P.K.F.). We are grateful for partial support of Aventis Pharma
(to P.K.F.). We are indebted to the COST-D24 programme for their support
(project number D24/0003/01). We thank Prof. S. Gladiali (Sassari) for
advice and Prof. A. Alexakis for the gift of 7 and for determining the ee of
our muscone sample. We are grateful to Dr Victor Garcia-Ruiz for
checking one of the stereochemical correlations.
ˆ
(C O), the signals at 27.0, 27.1 and 30.7 show fine structure due to the
À
presence of diastereotopic carbons; IR (liquid film): nÄmax ˆ 2924 (s, C H),
2852 (s, C H), 1717 (s, C C), 1448 (m), 1357 (m), 1164 (m), 890cm À1 (w);
À
ˆ
‡
found (HRMS, EI) ˆ 168.150677 [M ], C11H20O requires M 168.15141.
(R)-(‡)-5-Methyldecan-3-one (4g): Isolated yield 52%; oil; [a]2D4 ˆ ‡5.6
1
(c ˆ 1.07, CDCl3, 80 %ee); H NMR (400.1 MHz, CDCl3) d ˆ 0.88 (d, J ˆ
6.6, 3H; nPentCHMe) overlapped by 0.89 (t, J ˆ 6.9, 3H; (CH2)4Me), 1.05
(t, J ˆ 7.3, 3H; MeCH2CO), 1.10 1.36 (m, 8H; (CH 2)4), 1.20 1.35, 1.97
2.05 (m, 1H; CHMe), 2.20(dd, J ˆ 15.6, 8.0, 1H; CH2aCOEt), 2.37 (dd, J ˆ
15.6, 5.7, 1H; CH2bCOEt) overlapped by 2.40(dq, J ˆ 10.6, 2.4, 2H;
MeCH2CO); 13C NMR (100.6 MHz, CDCl3) d ˆ 8.2 (Me), 14.5 (Me), 20.3
[1] Synthetic reviews: N. Krause, A. Hoffmann-Roder, Synthesis 2001,
171 196, and references therein.
[2] Mechanistic reviews: a) E. Nakamura, S. Mori, Angew. Chem. 2000,
112, 3902 3924; Angew. Chem. Int. Ed. 2000, 39, 3750 3771; b) S.
Woodward, Chem. Soc. Rev. 2000, 29, 393 401.
[3] A. Alexakis, J. Vastra, J. Burton, P. Mangeney, Tetrahedron: Asym-
metry 1997, 8, 3193 3196; K. Soai, T. Hayasaka, S. Ugajin, J. Chem.
Soc. Chem. Commun. 1989, 516 517.
ˆ
(Me), 23.0, 27.0, 29.7, 32.4, 36.9, 37.4, 50.4 216.2 (C O); IR (liquid film):
À
À
À
ˆ
nÄmax ˆ 2957 (s, C H), 2927 (s, C H), 2872 (s, C H), 2866 (s), 1716 (s, C C),
1459 (m), 1412 (w), 1376 (m), 1106 (m), 725 cmÀ1 (w); found (HRMS, EI) ˆ
‡
170.166296 [M ], C11H22O requires M 170.167066.
[4] I. H. Escher, A. Pfaltz, Tetrahedron 2000, 56, 2879 288; S. J. Degrado,
H. Mizutani, A. H. Hoveyda, J. Am. Chem. Soc. 2001, 123, 755 756.
[5] B. L. Feringa, Acc. Chem. Res. 2000, 33, 346 353.
[6] C. Bolm, M. Ewald, M. Felder, Chem. Ber. 1992, 125, 1205 1215.
[7] H. Mizutani, S. J. Degrado, A. H. Hoveyda, J. Am. Chem. Soc. 2002,
124, 779 781.
[8] S. Woodward, Tetrahedron 2002, 58, 1017 1050, especially section 5.3.
[9] S. M. Azad, S. M. W. Bennett, J. Green, E. Sinn, C. M. Topping, S.
Woodward, S. M. Brown, J. Chem. Soc. Perkin Trans. 1 1997, 689 694.
[10] S. M. W. Bennett, S. M. Brown, A. Cunningham, M. R. Dennis, J. P.
Muxworthy, M. A. Oakley, S. Woodward, Tetrahedron 2000, 56, 2847
2855.
[11] M. Takahashi, K. Ogasawara, Tetrahedron: Asymmetry 1997, 8, 3125
3130.
[12] As far as we are aware Corey has been the only one to specifically
address this point: E. J. Corey, R. Naef, F. J. Hannon, J. Am. Chem.
Soc. 1986, 108, 7114 7116.
[13] P. L. Bryant, C. R. Harwell, A. A. Mrse, E. F. Emery, Z. Gan, T.
Caldwell, A. P. Reyes, P. Kuhns, D. W. Hoyt, L. S. Simeral, R. W. Hall,
L. G. Butler, J. Am. Chem. Soc. 2001, 123, 12009 12017; V. N.
Panchenko, V. A. Zakharov, I. G. Danilova, E. A. Paukshtis, I. I.
Zakharov, V. G. Goncharov, A. P. Suknev, J. Mol. Catal. A 2001, 174,
107 117.
[14] L. S. Hegedus, P. M. Kendall, S. M. Lo, J. R. Sheats, J. Am. Chem. Soc.
1975, 97, 5448 5452.
[15] D. A. Evans, M. D. Ennis, D. J. Mathre, J. Am. Chem. Soc. 1982, 104,
1737 1739; V. Garcia-Ruiz, S. Woodward, Tetrahedron: Asymmetry
2002, 13, 2177 2180.
(‡)-2,6-Dimethylundecan-4-one (4h): Isolated yield 54%; oil; [a]2D4 ˆ ‡2.8
(c ˆ 1.08 in CHCl3, 79% ee); 1H NMR (400.1 MHz, CDCl3) d ˆ 0.88 (d, J ˆ
6.6, 3H; nPentCHMe) overlapped by 0.88 (t, J ˆ 6.8, 3H; (CH2)4Me), 0.915
(d, J ˆ 6.7, 3H; CHMe2a) overlapped by 0.92 (d, J ˆ 6.7, 3H; CHMe2b),
1.10 1.35 (m, 8H; (CH 2)4), 2.00 (m, 1H; CHMe), 2.14 (m, 1H;
CH2CHMe2) overlapped by 2.18 (dd, J ˆ 15.8, 8.0, 1H; CH2aCOiBu),
2.26 (d, J ˆ 7.1, 2H; COCH2iPr), 2.35 (dd, J ˆ 15.8, 5.6, 1H; CH2bCOiBu);
13C NMR (100.6 MHz, CDCl3) d ˆ 14.5 (Me), 20.3 (Me), 23.0 (3C), 24.9,
ˆ
27.0, 29.6, 32.4, 37.3, 51.2, 52.8; C O signal not apparent at signal-to-noise
À
À
level in spectrum; IR (liquid film): nÄmax ˆ 2956 (s, C H), 2927 (s, C H),
2872 (s, C H), 1712 (s, C C), 1467 (m), 1366 (m), 1144 (w), 1044 cmÀ1 (w),
À
ˆ
‡
found (HRMS, EI) ˆ 198.197378 [M ], C13H26O requires M 198.198366.
(À)-2,5-Dimethyldecan-3-one (4i): Isolated yield 62%; oil; [a]2D4 ˆ À8.9
(c ˆ 1.12 in CHCl3, 68% ee); 1H NMR (400.1 MHz, CDCl3) d ˆ 0.87 (d, J ˆ
6.7, 3H; nPentCHMe) overlapped by 0.88 (t, J ˆ 6.9, 3H; (CH2)4Me), 1.08
(d, J ˆ 6.9, 6H; CHMe2), 1.20 1.35 (m, 8H; (CH 2)4), 2.02 (m, 1H;
CH2CHMe), 2.26 (dd, J ˆ 16.2, 8.0, 1H; CH2aCOiPr), 2.41 (dd, J ˆ 16.2, 5.7,
1H; CH2bCOiPr), 2.58 (septet, J ˆ 6.9, 1H; CHMe2); 13C NMR
(100.6 MHz, CDCl3) d ˆ 14.5 (Me), 18.5 (CHMea), 18.6 (CHMeb), 20.3,
ˆ
23.0, 27.1, 29.4, 32.4, 37.3, 41.5, 48.4, 216.0 (C O); IR (liquid film): nÄmax
ˆ
À
À
À
À
2961 (s, C H), 2928 (s, C H), 2872 (m, C H), 2857 (m, C H), 1711 (s,
À1
ˆ
C C), 1466 (m), 1381 (m), 1032 (w), 725 cm (w); found (HRMS, EI) ˆ
‡
184.182085 [M ], C12H24O requires M 184.182716.
(‡)-1-Cyclohexyl-1,5-dimethylhexan-4-one (4j): Isolated yield 59%; oil;
[a]2D4 ˆ ‡1.4 (c ˆ 1.06, CDCl3, 78% ee); 1H NMR (500.1 MHz, CDCl3) d ˆ
0.83 (d, J ˆ 6.8, 3H; CyCHMe), 0.91 (d, J ˆ 6.8, 3H; CHMe2) overlapped by
0.92 (d, J ˆ 6.8, 3H; CHMe2), 0.92 1.05 (m, 2H; Cy), 1.06 1.25 (m, 4H;
Cy), 1.58 (m, 3H; Cy), 1.70 1.78 (m, 2H; Cy), 1.92 (m, 1H; Cy CHMe), 2.14
(septet, J ˆ 6.8, 1H; CHMe2) overlapped by 2.16 (dd, J ˆ 15.7, 9.1, 1H;
CHCH2aCOiBu), 2.26 (d, J ˆ 6.8, 2H; COCH2iPr), 2.41 (dd, J ˆ 15.7, 4.6,
1H; CHCH2bCOiBu); 13C NMR (100.6 MHz, CDCl3) d ˆ 16.8 (Me), 22.8
[16] G. Bram, D. Cabaret, N. Maigrot, J.-P. Mazaleyrat, Z. Welvart, J.
Chem. Res. 1979, 196 197.
[17] P. K. Fraser, S. Woodward, Tetrahedron Lett. 2001, 42, 2747 2749.
[18] A. Alexakis, C. Benhaim, S. Rosset, M. Humam, J. Am. Chem. Soc.
2002, 124, 5262 5263.
ˆ
(2Me), 24.7, 26.9, 29.2, 30.6, 34.2, 42.9, 48.3, 52.7, 211.5 (C O), the signals at
22.8 and 26.9 show fine structure due to the presence of diastereotopic
[19] A. Alexakis, C. Benhaim, X. Fournioux, A. van den Heuvel, J.-M.
Leveque, S. March, S. Rosset, Synlett 1999, 1811 1813.
À
À
carbons; IR (liquid film): nÄmax ˆ 2955 (s, C H), 2925 (s, C H), 2852 (s,
782
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0903-0782 $ 20.00+.50/0
Chem. Eur. J. 2003, 9, No. 3

Addition of AlMe3 to Enones
776 783
[20] Up to 68% stereoselectivity was reported by Iwata×s group: Y.
Takemoto, S. Kuraoka, N. Hamaue, C. Iwata, Tetrahedron: Asymmetry
1996, 7, 993 996. Typically the selectivities realised in catalytic
asymmetric additions of AlR3 reagents is poor. For example, compare
ZnEt2 with AlEt3 in: A. Alexakis, C. Benhaim, Tetrahedron:
Asymmetry 2001, 12, 1151 1157.
[25] P. Salvadori, C. Rosini, D. Pini, C. Bertucci, P. Altemura, G. Uccello-
Barretta, A. Raffaelli, Tetrahedron 1987, 43, 4969 4978.
[26] A.-M. Loiseau, R. Luft, S. Zunino, Bull. Soc. Chim. Fr. 1982, 144 152.
[27] J. O. Metzger, M. Blumenstein, Chem. Ber. 1993, 126, 2493 2499.
[28] H. Tokuyama, S. Yokoshima, T. Yamashita, T. Fukuyama, Tetrahedron
Lett. 1998, 39, 3189 3192.
[21] G. J. Kubas, Inorg. Synth. 1990, 28, 68 70.
[29] A. Hinnen, J. Dreux, Bull. Chem. Soc. Fr. 1964, 1492 1498.
[30] G. A. Talstikov, F. Kh. Valitov, A. V. Kuchin, Zh. Obshch. Khim. 1980,
50, 2715 2720[ Chem. Abs. 1981, 94, 174234].
[31] V. Rautenstrauch, R. L. Snowden, S. M Linder, Helv. Chim. Acta 1990,
73, 896 901.
[22] S. M. W. Bennett, M. R. Dennis, P. K. Fraser, C. M. Topping, S. M.
Brown, S. Radojevic, G. Conole, J. Chem. Soc. Perkin 1 Trans. 1999,
3127 3132.
[23] C. Bˆrner, M. R. Dennis, E. Sinn, S. Woodward, Eur. J. Org. Chem.
2001, 2435 2436.
[24] O. De Lucchi, D. Fabri, Synlett 1990, 287 289.
Received: August 14, 2002 [F4343]
Chem. Eur. J. 2003, 9, No. 3
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0903-0783 $ 20.00+.50/0
783