A superior, readily available enantiopure ligand for the catalytic enantioselective addition of diethylzinc to a-substituted aldehydes

Article abstract of DOI:10.1021/jo981336i

The lithium perchlorate-induced ring opening of (S)-triphenylethylene oxide (3) with secondary amines (piperidine (a), N-methylpiperazine (b), AT-phenylpiperazine (c) and morpholine (d)) takes place in a stereospecific and completely regioselective manner to afford CR)-2-(dialkylamino)-l, 1, 2-triphenylethanols (4a-d). These amino alcohols catalytically induce the addition of diethylzinc to benzaldehyde with high enantioselectivity at 0 °C and at room temperature. Ligand 4a, which provides the highest enantioselectivity at 0 °C, has been studied in the addition of Et2Zn to a family of 20 representative aliphatic and aromatic aldehydes 5a-t. For a 17-membered set of a-substituted substrates (5a-m, q-t), including ortho-, meta-, and para-substituted benzaldehydes, the naphthaldehydes, ct./i?-unsaturated and aliphatic (cyclic and acyclic) aldehydes, the mean enantiomeric excess of the resulting alcohols 6a-m, q-t is 97%, whereas for three a-unsubstituted specimens (5n-p) the addition takes place with an enantioselectivity of 92-93%.

Full text of DOI:10.1021/jo981336i

7
078
J . Org. Chem. 1998, 63, 7078-7082
A Su p er ior , Rea d ily Ava ila ble En a n tiop u r e Liga n d for th e
Ca ta lytic En a n tioselective Ad d ition of Dieth ylzin c to
r-Su bstitu ted Ald eh yd es
†
†
†
†
Llu ´ı s Sol a` , Katamreddy Subba Reddy, Anton Vidal-Ferran, Albert Moyano,
,
†
†
‡
‡
Miquel A. Peric a` s,* Antoni Riera, Angel Alvarez-Larena, and J oan-F. Piniella
Unitat de Recerca en S ´ı ntesi Asim e` trica, Departament de Qu ´ı mica Org a` nica, Universitat de Barcelona,
c/ Mart ı´ i Franqu e` s, 1-11, 08028 Barcelona, Spain, and Unitat de Cristal‚lografia, Facultat de Ci e` ncies,
Universitat Aut o` noma de Barcelona, 08193 Barcelona, Spain
Received J uly 8, 1998
The lithium perchlorate-induced ring opening of (S)-triphenylethylene oxide (3) with secondary
amines (piperidine (a ), N-methylpiperazine (b), N-phenylpiperazine (c) and morpholine (d )) takes
place in a stereospecific and completely regioselective manner to afford (R)-2-(dialkylamino)-1,1,2-
triphenylethanols (4a -d ). These amino alcohols catalytically induce the addition of diethylzinc to
benzaldehyde with high enantioselectivity at 0 °C and at room temperature. Ligand 4a , which
2
provides the highest enantioselectivity at 0 °C, has been studied in the addition of Et Zn to a family
of 20 representative aliphatic and aromatic aldehydes 5a -t. For a 17-membered set of R-substituted
substrates (5a -m ,q-t), including ortho-, meta-, and para-substituted benzaldehydes, the naph-
thaldehydes, R,â-unsaturated and aliphatic (cyclic and acyclic) aldehydes, the mean enantiomeric
excess of the resulting alcohols 6a -m ,q-t is 97%, whereas for three R-unsubstituted specimens
(5n -p ) the addition takes place with an enantioselectivity of 92-93%.
In tr od u ction
Despite the ever-increasing repertoire of metal-cata-
refinement leading to ligand 1a through mechanism-
guided molecular design.4 We wish to report now on the
identification of a superior, general ligand for the enan-
tioselective addition of diethylzinc to R-substituted alde-
hydes, among the products arising from the completely
regioselective ring-opening with secondary amines of (S)-
triphenylethylene oxide (3). This reagent, in turn, is
readily available in enantiopure form at the molar scale
through J acobsen epoxidation of inexpensive triphenyl-
lyzed asymmetric organic reactions available to chemists,
the chiral amino alcohols ubiquitously employed as
ligands in these processes are still mostly based on a few
naturally occurring skeletons, thus belonging to a limited
number of structural types.1 It is virtually impossible
that such a limited set of ligands can satisfactorily cope
with all of the conceivable situations (diversity of metals,
substrates, and reagents) in catalysis. The synthesis of
new ligands, based on processes that are compatible with
structural diversity, is thus a matter of enormous inter-
est. When the preparation of â-amino alcohols is scru-
tinized under the prism of diversity, the regioselective
and stereospecific ring opening of epoxides with nitrogen
nucleophiles appears as the method of choice. If enan-
tiopurity of the target amino alcohols is an additional
requirement, the current availability of synthetic meth-
5
ethylene followed by enantiomeric enrichment by crys-
tallization.6
2
3
ods such as the Sharpless and J acobsen epoxidations
for the catalytic production of enantiomerically pure
epoxides of great structural diversity provides a satisfac-
tory answer to this demand.
Resu lts a n d Discu ssion
To define our initial space of candidate structures, the
dialkylamino moiety was restricted to cyclic, six-mem-
bered ring secondary amines, which have provided the
highest enantioselectivities in ligands 1.4 The ring-
opening processes were initially performed in the pres-
We have recently reported the synthesis of a family of
fine-tunable â-amino alcohol ligands (1), based on enan-
tiopure epoxycinnamyl alcohol (2) and its structural
7
ence of lithium perchlorate according to Crotti (condi-
*
To whom correspondence should be addressed. E-mail: mpb@
tions A in Scheme 1). Epoxide 3 behaved in these
ursa.qo.ub.es.
†
Unitat de Recerca en S ´ı ntesi Asim e` trica.
Unitat de Cristal‚lografia.
‡
(4) (a) Vidal-Ferran, A.; Moyano, A.; Peric a` s, M. A.; Riera, A. J . Org.
Chem. 1997, 62, 4970-4982. (b) Vidal-Ferran, A.; Moyano, A.; Peric a` s,
M. A.; Riera, A. Tetrahedron Lett. 1997, 38, 8773-8776.
(5) Brandes, B. D.; J acobsen, E. N. J . Org. Chem. 1994, 59, 4378-
4380.
(1) For general reviews, see: (a) Chiral Auxiliaries and Ligands in
Asymmetric Synthesis; Seyden-Penne, J ., Ed.; J ohn Wiley & Sons: New
York, 1995. (b) Blaser, H. U. Chem. Rev. 1992, 92, 935-952.
(2) For reviews, see: (a) Katsuki, T.; Mart ´ı n, V. S. Org. React. 1996,
4
8, 1-299. (b) J ohnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; VCH Publishers: New York, 1993; pp 101-
58.
3) J acobsen, E. N. In Catalytic Asymmetric Synthesis; Ojima, I.,
Ed.; VCH Publishers: New York, 1993; pp 159-202.
(6) (S)-Triphenylethylene oxide (3) is obtained in 94% ee following
J acobsen’s epoxidation procedure and can be enantiomerically enriched
by a single recrystallization from hexane up to >99.9% ee.
(7) Chini, M.; Crotti, P.; Flippin, L. A.; Gardelli, C.; Giovani, E.;
Macchia, F.; Pineschi, M. J . Org. Chem. 1993, 58, 1221-1227.
1
(
S0022-3263(98)01336-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/11/1998

Addition of Diethylzinc to R-Substituted Aldehydes
J . Org. Chem., Vol. 63, No. 20, 1998 7079
Sch em e 1
Ta ble 1. Lith iu m P er ch lor a te-In d u ced Rin g Op en in g of
(
S)-Tr ip h en yleth ylen e Oxid e w ith Secon d a r y Am in es
â-amino
alcohol
condn Aa
yield (%)
condn Ba
yield (%)
amine
piperidine
4a
4b
4c
4d
4e
92
54
28
98
96
96
86
0
N-methylpiperazine
N-phenylpiperazine
morpholine
c
Sch em e 2
cis-2,6-dimethylpiperidine
a
Reaction in acetonitrile at reflux for 24 h in the presence of
b
the amine (10 equiv) and lithium perchlorate (15 equiv). Reaction
in excess amine at 100 °C for 24 h in the presence of lithium
perchlorate (2 equiv). c By extending reaction time to 72 h, yield
can be improved to 44%, and a 50% amount of the starting
material is recovered unchanged.
reactions as a highly congested substrate, with satisfac-
tory results being only recorded in the case of piperidine.
However, after some experimentation, we found that
much better results were obtained if the reaction was
perfomed in excess amine in the presence of only 2 equiv
of lithium perchlorate at 100 °C (conditions B in Scheme
observed. This could, however, be increased to 92-93%
by simply performing the addition reaction at -20 °C.
The results obtained with ortho-substituted benzalde-
hydes, along with the fact that the addition to aromatic
aldehydes mediated by 4a appears to be completely
insensitive to the electronic nature (electron donating or
electron withdrawing) of the substituents, suggested that
the decrease in enantioselectivity with 5n -p could be
simply due to the absence of substitution at the R carbon.
To test this hypothesis, we also studied the addition to
the R-substituted aliphatic aldehydes 5q-s and to R-me-
thylcinnamaldehyde 5t, which cover both cyclic and
acyclic substrates. Gratifyingly enough, the enantiomeric
purity of the resulting alcohols was again very high (95-
1
). Even under these improved conditions, the rather
hindered cis-2,6-dimethylpiperidine failed to provide
amino alcohol 4e, but for the other studied amines, amino
alcohols 4a -c were obtained in excellent yield. In all
the studied cases, the reactions were completely regiose-
lective, and the precise regiochemistry could be estab-
lished by X-ray diffraction in the case of 4b.8 Also for
4
b, HPLC analysis on a chiral column showed that the
ring-opening process takes place with complete ste-
reospecificity.9
Ligands 4a -d were initially tested in the enantiose-
lective addition of diethylzinc to benzaldehyde (5a ).10
Whereas all four ligands are essentially equivalent at
room temperature, affording (S)-6a of 92-93% ee, 4a
shows a very interesting enantioselectivity/temperature
profile, a 6% increase in the ee of 6a being recorded by
simply lowering the reaction temperature to 0 °C.11
Moreover, this ligand exhibits a very high catalytic
activity, the reaction being essentially complete (98%
conversion) after only 0.5 h at 0 °C. If desired, the
amount of ligand can be lowered to 2%, the reaction then
requiring 4 h for 99% conversion without significant loss
9
9%).
Given the large number of species that have been used
to catalyze with more or less success the enantioselective
addition of diethylzinc to aldehydes, a solid assessment
of the merits of 4a requires a comparison of availability,
experimental conditions involved in use, and overall
performance with previously known ligands. To allow
this comparison, we have collected in Table 3 relevant
information on the characteristics of some of the most
13
popular ligands for this chemistry.
The simple inspection of Table 3 reveals that 4a is
placed at the top among these ligands in mean enantio-
meric excess despite the large family of aldehydes it has
been studied with. Even more importantly, the standard
(ca. 1%) in enantioselectivity.
Ligand 4a was subsequently employed to induce the
enantioselective addition of diethylzinc to a representa-
tive family of aromatic aldehydes 5b-m (Scheme 2 and
Table 2). Very interestingly, the enantiomeric purity of
the resulting S alcohols was in all cases higher than
n
deviation (σ ) in ee when using 4a is extremely small,
specially when the 17-membered set of R-substituted
aldehydes is considered. This means, in practice, that
when the enantioselective addition of diethylzinc to one
such aldehyde is considered, the use of 4a can be decided
with almost absolute confidence.14
9
5%.12 Most remarkable are the results with ortho-
substituted benzaldehydes and with 1-naphthaldehyde,
since these more congested substrates tend to experience
dialkylzinc addition with comparatively lower enantiose-
(
13) (a) Schmidt, B.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1991,
lectivity than other aromatic substrates.1
3j,l
We next
3
0, 1321-1323. (b) Schmidt, B.; Seebach, D. Angew. Chem., Int. Ed.
tested the reaction on aliphatic aldehydes 5n -p : In these
cases, a slightly lower (90-92%) enantioselectivity was
Engl. 1991, 30, 99-101. (c) Soai, K.; Yokoyama, S.; Hayasaka, T. J .
Org. Chem. 1991, 56, 4264-4268. (d) Soai, K.; Yokoyama, S.; Ebihara,
K.; Hayasaka, T. J . Chem. Soc., Chem. Commun. 1987, 1690-1. (e)
Soai, K.; Ookawa, A.; Kaba, T.; Ogawa, K. J . Am. Chem. Soc. 1987,
109, 7111-7115. (f) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J .
Am. Chem. Soc. 1986, 108, 6071-6072. (g) Watanabe, M.; Araki, S.;
Butsugan, Y. J . Org. Chem. 1991, 56, 2218-2224. (h) Kang, J .; Lee,
J . W.; Kim, J . I. J . Chem. Soc., Chem. Commun. 1994, 2009-2010. (i)
Kang, J .; Kim, D. S.; Kim, J . I. Synlett 1994, 842-844. (j) Qiu, J .; Guo,
C.; Zhang, X. J . Org. Chem. 1997, 62, 2665-2668. (k) Zhang, F. Y.;
Chan, A. S. C. Tetrahedron: Asymmetry 1997, 8, 3651-3655. (l) Huang,
W. S.; Hu, Q. S.; Pu, L. J . Org. Chem. 1998, 63, 1364-1365. (m) For
the use of bis-sulfonamides derived from enantiomerically pure trans-
1,2-diaminocyclohexane as ligands for the highly efficient addition of
diethylzinc to a limited set of aldehydes (four specimens), see: Taka-
hashi, H.; Kawakita, T.; Ohno, M.; Yoshioka, M.; Kobayashi, S.
Tetrahedron 1992, 48, 5691-5700.
(8) The authors have deposited atomic coordinates for this structure
with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, U.K.
(
9) The ring-opening process was assumed to occur with complete
stereospecifity in the other substrates.
10) For reviews, see: (a) Soai, K. Chem. Rev. 1992, 92, 833-856.
b) Noyori, R. Asymmetric Catalysis in Organic Synthesis; J ohn Wiley
Sons: New York, 1994; pp 255-297.
11) A 2-3% increase in ee was observed with 4b-d under similar
conditions.
(
(
&
(
(12) The S configuration was established by comparison of the
optical rotation with published values and, for 6t, by comparison of
retention times of the corresponding acetate derivative (GC, â-DEX
column). For 6b,f,h ,r the S configuration has been assumed.
(14) The configuration of the resulting alcohols is in agreement with
Noyori’s empirical rule. See ref 10b, pp 265-266.

7
080 J . Org. Chem., Vol. 63, No. 20, 1998
Sol a` et al.
Ta ble 2. Ca ta lytic En a n tioselective Ad d ition of Et2Zn to Ald eh yd es 5a -t Lea d in g to Alcoh ols 6a -t Med ia ted by
Liga n d 4a
resulting
alcohol
conversiona
(%)
selectivityb
(%)
enant
excess (%)
c
starting aldehyde
benzaldehyde (5a )
o-chlorobenzaldehyde (5b)
o-fluorobenzaldehyde (5c)
o-tolualdehyde (5d )
o-methoxybenzaldehyde (5e)
m-fluorobenzaldehyde (5f)
m-tolualdehyde (5g)
m-methoxybenzaldehyde (5h )
p-fluorobenzaldehyde (5i)
p-tolualdehyde (5j)
(S)-6a
(S)-6b
(S)-6c
(S)-6d
(S)-6e
(S)-6f
(S)-6g
(S)-6h
(S)-6i
(S)-6j
(S)-6k
(S)-6l
(S)-6m
(S)-6n
100
100
99
100
99
99
99
99
99
98
99
97
92
97
99
100
99
100
98
98
95
96
97
96
97
97
97
98
100
100
98
98
98
>99
p-methoxybenzaldehyde (5k )
1
2
-naphthaldehyde (5l)
-naphthaldehyde (5m )
99
99
99
100
99
99
99
100
99
99
98
92
92
93
e
e
e
heptanal (5n )
isovaleraldehyde (5o)
d
e
e
e
(S)-6o
e
e
e
3
-phenylpropanal (5p )
(S)-6p d
(S)-6q
(S)-6r
(S)-6s
(S)-6t
cyclohexanecarbaldehyde (5q)
99
99
99
88
98
99
99
99
98
99
3
2
-cyclohexenecarbaldehyde (5r )f
-ethylbutyraldehyde (5s)
g
97
95
(E)-R-methylcinnamaldehyde (5t)
a
Determined by integration of residual 5 in front of all new products in the gas chromatogram of the reaction crude. b Determined by
c
integration of 6 (both enantiomers) in front of all new compounds in the gas chromatogram of the reaction crude. Determined by GC on
a â-DEX 120 column. Reaction was performed at -20 °C. e Determined by GC on a R-DEX 120 column. f Commercial, racemic compound
d
g
was used. Diastereomeric excess for both enantiomers of starting material.
Ta ble 3. Com p a r a tive An a lysis of Liga n d s for th e
En a n tioselective Ad d ition of Et2Zn to Ald eh yd es
In contrast, other ligands in Table 3 with similar
performance are only available through lengthy se-
quences from expensive starting materials1 or have to
be prepared immediately prior to use due to stability
problems.1
All these characteristics should contribute to the
introduction of 4a as a synthetic reagent. Extension of
the use of 4a as a ligand in related processes is underway
in our laboratories. Results will be reported in due
course.
3l
conditions of use
performance
mean
no. of
tested
%
T (°C)/
t(h)
σ
3a,b
entry
ligand
mol
aldehydes ee (%) (%)
1
1
3a
1
2
3
4
5
6
7
8
9
Seebach
Seebach
20
10
6
2
2
5
5
20
20
-22/15
9
9
7
7
6
10
12
16
14
23
17
20
97.6
91.4
89.3
91.3 11.6
88.7 12.7
89.3 14.0
95.9
90.8 11.9
94.0
96.5
97.3
96.6
2.4
5.6
5.4
3b
-75/15-24
1
1
3c,d
3e
Soai
Soai
Noyori
0/16
0/a
1
3f
0/6-64
25/1-4
0/8-12
-23/4
0/5
1
3g
Butsugan
1
3h,i
Kang
7.5
1
3j
Zhang
Exp er im en ta l Section
Gen er a l Meth od s. 1H NMR and 13C NMR spectra were
recorded in CDCl at 300 and 75.4 MHz, respectively. El-
3
emental analyses were carried out by the Servei d’An a` lisis
Elementals del C.S.I.C. de Barcelona. Optically pure com-
1
3k
Chan
4.0
2.8
1.3
2.2
1
3l
1
1
1
0
1
2
Pu
5-30 0/4-45
6
6
b
c
4a , this work
4a , this work
0/3
-20 or 0/3-4
a
Not reported. b For R-substituted aldehydes. c For the full set
of studied aldehydes.
pound (S)-triphenylethylene oxide (3) was prepared according
to the procedure described by J acobsen et al.5 followed by
recrystallization.
Lit h iu m P er ch lor a t e-In d u ced R egioselect ive R in g
Op en in g of (S)-Tr ip h en yleth ylen e Oxid e (3). Meth od A.
If we attend to conditions of use, 4a is again one of
the most favorable options. Thus, ligands in entries 1
and 10 (Table 3), which are considered to be among the
best for this particular process, require for high enanti-
oselectivity either the use of substantially higher amounts
of catalyst at unconveniently low temperatures or ex-
tended reaction periods. With a 6% molar amount of
ligand 4a (Table 3, entry 11), in turn, conversions higher
than 95% are recorded after 1 h at 0 °C, and the reactions
are complete after 3 h at that temperature (see Table 3).
Also in this respect, an additional practical advantage
(
(
(
R)-2-P ip er id in o-1,1,2-tr ip h en yleth a n ol (4a ). Piperidine
1.7 mL, 17 mmol) was added via syringe into a mixture of
S)-3 (0.50 g, 1.84 mmol) and LiClO
The resulting mixture was
heated at 80 °C. After 24 h, the solution was cooled to room
temperature, and CH Cl (25 mL) was added. The organic
4
(2.93 g, 27.6 mmol) in
2
acetonitrile (2 mL) under N .
2
2
layer was washed with H O (2 × 25 mL), dried, and concen-
2
trated in vacuo. The residual solid was purified by chroma-
tography in SiO
2 3
/Et N (2.5% v/v) using hexane/EtOAc (100:
0
-95:5) as eluent to give 0.61 g (92%) of (R)-4a as white
2
3
1
crystals: mp 158 °C; [R]
D
) -141.5 (c ) 0.755 in CHCl
) δ 7.65 (d, J ) 7.2 Hz, 2H), 7.00-7.30
m, 13H), 5.85 (brs, 1H), 4.52 (s, 1H), 2.35-2.40 (m, 2H), 2.00-
3
); H
of ligand 4a is that the use of additives, such as titanium
NMR (300 MHz, CDCl
(
2
3
alkoxides,1
3a,b,j-m
is not required for the achievement of
high enantiomeric excesses.
13
.10 (m, 2H), 1.37-1.44 (m, 4H), 1.25-1.29 (m, 2H); C NMR
) δ 149.3 (C), 145.8 (C), 137.3 (C), 131.3 (CH),
27.9 (CH), 127.4 (CH), 127.2 (CH), 126.8 (CH), 126.2 (CH),
25.6 (CH), 78.6 (C), 77.7 (CH), 54.4 (CH ), 26.8 (CH ), 24.1
); IR (KBr) 3475, 3100, 3050, 3025, 2937, 2800, 1493, 1449,
A final aspect to be considered is the ease of prepara-
tion of the different ligands. Again in this respect, 4a
reveals as a superior option. Thus, amounts of this
ligand in the 0.1-1.0 mol range can be prepared from
inexpensive triphenylethylene in just a few days work
through a very simple, two-step sequence taking place
in 95% overall yield. Moreover, the enantiomerically
pure ligand is a completely stable, highly crystalline solid.
(75 MHz, CDCl
3
1
1
2
2
(CH
2
-
1
1
034, 972, 751, 700, 635 cm ; MS (CI, NH
3
) m/z 358 (C25
27
H -
+
NO‚H , 100). Anal. Calcd for C25
N, 3.92. Found: C, 83.99; H, 7.62; N, 3.91.
H27NO: C, 83.99; H, 7.61;
(R)-2-(4-Meth ylp ip er a zin -1-yl)-1,1,2-tr ip h en yleth a n ol
(4b). A mixture of (S)-3 (0.27 g, 1.00 mmol), LiClO (1.65 g,
4

Addition of Diethylzinc to R-Substituted Aldehydes
5.5 mmol), and N-methylpiperazine (1.1 mL, 10 mmol) in CH
CN (2.5 mL) was heated at 80 °C during 24 h and treated as
described for 4a to give 0.20 g (54%) of (R)-4b as white
crystals: The enantiomeric purity was determined by HPLC
analysis (column, Chiralcel-OD; eluent, hexane/2-propanol 99:
J . Org. Chem., Vol. 63, No. 20, 1998 7081
1
3
-
(1 mmol) at room temperature. The mixture was stirred for
20 min and then cooled to the desired temperature if necessary.
Diethylzinc (2.2 mL of a 1 M hexanes solution, 2.2 mmol) was
added dropwise. The mixture was stirred for the correspond-
ing reaction time under N
the addition of a saturated NH
mixture was then extracted with CH
combined organic extracts were dried and concentrated in
vacuo. Conversion, selectivity, and enantiomeric purity of the
resulting alcohols was determined from the crude mixture by
GC analyses. Conditions of GC analyses: Supelco â-DEX or
R-DEX 120 column, 30 m length, 0.25 mm inner diameter,
isotherm temperature program, He as carrier gas (2.4 mL/
2
. The reaction was quenched by
Cl solution (10 mL). The
Cl
(3 × 10 mL), and the
1
; flow rate, 0.5 mL/min; R isomer, t
R
8.7 min, and S isomer,
4
2
3
t
R
11.2 min) and found to be >99.9%: mp 154 °C; [R]
D
)
2
2
1
-
121.6 (c ) 1.02 in CHCl
3
); H NMR (300 MHz, CDCl
3
) δ 7.77
(
d, J ) 8.7 Hz, 2H), 7.00-7.40 (m, 13H), 5.60 (s, 1H), 4.66 (s,
1
3
1
H), 2.30-2.50 (m, 8H), 2.22 (s, 3H); C NMR (75 MHz,
) δ 149.1 (C), 145.6 (C), 137.3 (C), 131.0 (CH), 128.0 (CH),
27.5 (CH), 127.2 (CH), 127.0 (CH), 126.4 (CH), 126.2 (CH),
25.6 (CH), 125.4 (CH), 78.6 (C), 76.6 (CH), 55.7 (CH ), 53.0
), 45.7 (CH ); IR (KBr) 3400, 2950, 2790, 1495, 1449, 1138,
001, 743, 704 cm-1; MS (CI, NH
00). Anal. Calcd for C25 O: C, 80.61; H, 7.57; N, 7.52.
CDCl
1
1
3
2
(CH
2
3
min). For 1-phenylpropanol: â-DEX 120 column, 112 °C, t
R isomer 49.3 min, t S isomer 52.0 min. For 1-(o-tolyl)-
propanol: â-DEX 120 column, 120 °C, t R isomer 59.1 min,
S isomer 63.8 min. For 1-(m-tolyl)propanol: â-DEX 120
column, 120 °C, t R isomer 52.2 min, t S isomer 53.8 min.
For 1-(p-tolyl)propanol: â-DEX 120 column, 120 °C, t
isomer 50.4 min, t S isomer 53.3 min. For 1-(2-methoxyphe-
nyl)propanol: â-DEX 120 column, 135 °C, t S isomer 48.1 min,
R isomer 54.1 min. For 1-(3-methoxyphenyl)propanol:
â-DEX 120 column, 135 °C, t R isomer 66.2 min, t S isomer
68.0 min. For 1-(4-methoxyphenyl)propanol: â-DEX 120
column, 135 °C, t R isomer 68.2 min, t S isomer 70.4 min.
For 1-(2-fluorophenyl)propanol: â-DEX 120 column, 112 °C,
R isomer 51.0 min, t S isomer 54.5 min. For 1-(3-
fluorophenyl)propanol: â-DEX 120 column, 112 °C, t R isomer
60.0 min, t S isomer 63.2 min. For 1-(4-fluorophenyl)-
propanol: â-DEX 120 column, 112 °C, t R isomer 57.3 min,
S isomer 61.2 min. For 1-(1-naphthyl)propanol: â-DEX 120
column, 160 °C, t S isomer 98.9 min, t R isomer 103.2 min.
For 1-(2-naphthyl)propanol: â-DEX 120 column, 160 °C, t
isomer 100.2 min, t S isomer 102.4 min. For 5-methyl-3-
hexanol: R-DEX 120 column, 65 °C, t R isomer 15.1 min, t
S isomer 15.5 min. For 1-(3-cyclohexenyl)propanol: â-DEX
120 column, 100 °C, t S isomer 69.8-70.6 min, t R isomer
74.2-74.4 min. For (E)-1-phenyl-2-methyl-pent-1-en-3-ol: (ac-
etate derivative) â-DEX 120 column, 140 °C, t S isomer 54.3
min, t R isomer 55.7 min. For 4-ethyl-3-hexanol: (acetate
derivative) â-DEX 120 column, 65 °C, t S isomer 46.9 min, t
R isomer 49.7 min. For 1-cyclohexylpropanol: R-DEX 120
column, 90 °C, t R isomer 41.7 min, t S isomer 43 min. For
3-nonanol: R-DEX 120 column, 70 °C, t R isomer 71.9 min,
S isomer 74.3 min. For 1-phenyl-3-pentanol: R-DEX 120
column, 118 °C, t R isomer 64.5 min, t S isomer 65.7 min.
R
+
1
1
3
) m/z 373 (C25
H
28
N
2
O‚H ,
R
H
28
N
2
R
Found: C, 80.46; H, 7.61; N, 7.53.
R )-2-(4-P h e n ylp ip e r a zin -1-yl)-1,1,2-t r ip h e n yle t h a -
n ol (4c). A mixture of (S)-3 (0.27 g, 1.00 mmol), LiClO (1.65
g, 15.5 mmol), and N-phenylpiperazine (1.53 mL, 10 mmol) in
CH CN (2.5 mL) was heated at 80 °C during 24 h and treated
as described for 4a to give 0.122 g (28%) of (R)-4c as white
t
R
(
R
R
4
R
R
R
3
R
t
R
2
3
1
crystals: mp 181 °C; [R]
D
) -92.6 (c ) 0.225 in CHCl
) δ 7.73 (d, J ) 8.4 Hz, 2H), 6.80-7.34
m, 18H), 5.40 (bs, 1H), 4.66 (s, 1H), 2.98-3.03 (m, 4H), 2.53-
3
); H
R
R
NMR (300 MHz, CDCl
3
(
2
1
R
R
.61 (m, 2H), 2.22-2.30 (m, 2H); 13C NMR (75 MHz, CDCl
51.0 (C), 149.0 (C), 145.6 (C), 137.2 (C), 131.0 (CH), 129.0
) δ
3
t
R
R
(
(
(
CH), 128.1 (CH), 127.7 (CH), 127.3 (CH), 127.1 (CH), 126.4
CH), 126.3 (CH), 125.7 (CH), 125.5 (CH), 119.6 (CH), 115.7
R
R
CH), 78.8 (C), 76.7 (CH), 53.0 (CH
450, 2830, 2800, 1599, 1495, 1449, 1237, 1001, 764, 700 cm
2
), 49.6 (CH
2
); IR (KBr)
R
-
1
3
;
t
R
+
MS (CI, NH
C
3
) m/z 435 (C30
O: C, 82.91; H, 6.96; N, 6.45. Found: C, 82.83; H,
H
30
N
2
O‚H , 100). Anal. Calcd for
R
R
30
H
30
N
2
R
R
6
.86; N, 6.44.
R
Lit h iu m P er ch lor a t e-In d u ced R egioselect ive R in g
Op en in g of (S)-3. Meth od B. (R)-2-P ip er id in o-1,1,2-tr i-
p h en yleth a n ol (4a ). A mixture of (S)-3 (10.88 g, 0.04 mol),
R
R
R
R
LiClO
heated at 100 °C under N
distilled under reduced pressure. The residue was dissolved
in CH Cl
(250 mL), washed with water (2 × 100 mL), dried
Na SO ), and concentrated under reduced pressure to give
crude product. The residual solid was purified by chromatog-
raphy in SiO /Et N (2.5% v/v) using hexane/EtOAc (100: 0-95:
) as eluent to afford 14.02 g (98%) of (R)-4a as white crystals.
R)-2-(4-Meth ylp ip er a zin -1-yl)-1,1,2-tr ip h en yleth a n ol
4b). A mixture of (S)-3 (0.50 g, 1.84 mmol), LiClO (0.39 g,
.67 mmol, 2 equiv) and N-methypiperazine (7.1 mL, 64 mmol,
5 equiv) was heated at 100 °C during 24 h and treated as
4
(8.5 g, 0.08 mol), and piperidine (40 mL, 0.4 mol) was
2
. After 24 h, the excess amine was
R
R
2
2
R
R
(
2
4
R
R
2
3
R
5
t
R
(
R
R
(
4
To establish the absolute configuration of the final com-
pounds, the alcohols were purified by bulb-to-bulb distillation
of the crude mixtures. The optical rotation was measured in
each case, and its sign was compared with the reported value
3
3
described for 4a to give 0.66 g (96%) of (R)-4b as white crystals.
R )-2-(4-P h e n ylp ip e r a zin -1-yl)-1,1,2-t r ip h e n yle t h a -
n ol (4c). A mixture of (S)-3 (0.54 g, 2.0 mmol), LiClO (0.42
1
3f
15a
(
(S)-1-phenylpropanol,
(S)-1-(o-tolyl)propanol,
(S)-1-(m-
1
5b
15c
4
tolyl)propanol, (S)-1-(p-tolyl)propanol, (R)-1-(2-methoxyphen-
yl)propanol,1 (S)-1-(4-methoxyphenyl)propanol, (R)-1-(2-fluor-
5d
15c
g, 4.0 mmol), and N-phenylpiperazine (3.1 mL, 20 mmol) was
heated at 100 °C during 24 h and treated as described for 4a
to give 0.83 g (96%) of (R)-4c as white crystals after chroma-
tography.
ophenyl)propanol,1 (R)-1-(4-fluorophenyl)propanol,
5e
13h
15g
(R)-1-
1
5f
(1-naphthyl)propanol, (R)-1-(2-naphthyl)propanol,
(S)-5-
methyl-3-hexanol,1 (S)-1-cyclohexylpropanol, (S)-3-nonanol,
3e
13d
15h
(S)-1-phenyl-3-pentanol,1 and (S)-4-ethyl-3-hexanol.
5i
13g
For
(
R)-2-Mor p h olin o-1,1,2-tr ip h en yleth a n ol (4d ). A mix-
ture of (S)-3 (0.50 g, 1.84 mmol), LiClO (0.39 g, 3.67 mmol, 2
4
(R)-(E)-1-phenyl-2-methylpent-1-en-3-ol retention times of ac-
1
3l
equiv) and morpholine (6 mL, 60 mmol, 35 equiv) was heated
at 100 °C during 24 h and treated as described for 4a to give
etate derivative were compared with reported values.
For
6b,f,h ,r , the absolute configuration was assumed to be S.
2
3
0
.57 g (86%) of (R)-4d as white crystals: mp 176 °C; [R]
D
)
(
b) Typ ica l P r oced u r e for P r ep a r a tive Exp er im en ts:
1
-
7
4
(
(
(
118.6 (c ) 0.545 in CHCl
3
); H NMR (300 MHz, CDCl
3
) δ
13d
(
S)-1-Cycloh exylp r op a n ol (6q).
To a solution of 4a (22
.70 (d, J ) 8.7 Hz, 2H), 7.00-7.30 (m, 13H), 5.42 (s, 1H),
.57 (s, 1H), 3.48-3.52 (m, 4H), 2.30-2.40 (m, 2H), 2.10-2.20
m, 2H); C NMR (75 MHz, CDCl ) δ 149 (C), 145.6 (C), 137.0
3
C), 131.0 (CH), 128.1 (CH), 127.6 (CH), 127.3 (CH), 127.2
CH), 126.4 (CH), 126.3 (CH), 125.6 (CH), 125.4 (CH), 78.7 (C),
mg, 0.06 mmol) in toluene (2 mL) was added cyclohexanecar-
baldehyde 5q (112 mg, 120 µL, 1 mmol) at ambient temper-
1
3
(
15) (a) Chelucci, G.; Conti, S.; Falorni, M.; Giacomelli, G. Tetrahe-
dron 1991, 47, 8251-8257. (b) Chaloner, P. A.; Perera, S. A. R.
Tetrahedron Lett. 1987, 28, 3013-3014. (c) Capillon, J .; Gu e´ tt e´ , J . P.
Tetrahedron 1979, 35, 1817-1820. (d) Smaardijk, A. A.; Wynberg, H.
J . Org. Chem. 1987, 52, 135-137. (e) Seebach, D.; Beck, A. K.; Schmidt,
B.; Wang, Y. M. Tetrahedron 1994, 50, 4363-4384. (f) Niwa, S.; Soai,
K. J . Chem. Soc., Perkin Trans. 1 1991, 2717-2720. (g) Oguni, N.;
Omi, T.; Yamamoto, Y.; Nakamura, A. Chem. Lett. 1983, 841-842.
h) Soai, K.; Niwa, S.; Watanabe, M. J . Org. Chem. 1988, 53, 927-8.
(i) Sato, T.; Gotoh, T.; Wakabayashi, Y.; Fujisawa, T. Tetrahedron Lett.
1983, 24, 4123-4126.
7
1
7.1 (CH), 67.3 (CH
2 2
), 53.7 (CH ); IR (KBr) 3450, 2846, 1495,
-
1
451, 1318, 1119, 999, 740, 704 cm ; MS (CI, NH
3
) m/z 360
: C, 80.19;
+
(C
24
H
25NO
2
‚H , 100). Anal. Calcd for C24
H
25NO
2
H, 7.01; N, 3.90. Found: C, 80.03; H, 7.01; N, 3.93.
En a n tioselective Am in o Alcoh ol-Ca ta lyzed Ad d ition
of Dieth yzin c to Ald eh yd es. (a ) Gen er a l P r oced u r e for
An a lytica l Exp er im en ts. To a solution of the chiral catalyst
(
(0.06 mmol, 6 mol %) in toluene (2 mL) was added the aldehyde

7
082 J . Org. Chem., Vol. 63, No. 20, 1998
Sol a` et al.
ature under N
cooled to 0 °C. Diethylzinc (2.2 mL of 1 M hexanes solution,
.2 mmol) was added dropwise over a period of 10 min. The
mixture was stirred for 3 h, by which time the starting
material disappeared (TLC). The reaction mixture was then
2
. The mixture was stirred for 20 min and then
to give 136 mg (96%) of 6q of 98% ee and 21 mg of 4a (95%
recovery).
2
Ack n ow led gm en t. We thank DGICYT (PB95-0265)
and CIRIT (1996SGR 00013) for financial support.
K.S.R. thanks MEC for a fellowship under the program
quenched by the addition of a saturated NH
mL) and extracted with CH Cl
(3 × 10 mL). The combined
organic extracts were washed with water (10 mL) and brine
10 mL) and dried (Na SO ) before concentration in vacuo to
4
Cl solution (10
“
Estancias Temporales de Cient ´ı ficos y Tecn o´ logos Ex-
2
2
tranjeros en Espa n˜ a” and A. V.-F. thanks MEC for a
contract under the program “Acciones para la Incorpo-
raci o´ n a Espa n˜ a de Doctores y Tecn o´ logos”.
(
2
4
afford crude 6q in quantitative yield. The addition product
and the ligand 4a were separated by column chromatography
J O981336I