(S)-(-)- and (R)-(+)-4-methyl-2-hydroxymethyl[2]paracyclo-[2](5,8)quinolinophane: Novel N,O-planar chiral catalysts for the enantioselective addition of diethylzinc to aldehydes

Article abstract of DOI:10.1055/s-2002-25350

Novel planar chiral N,O-ligands derived from (R)-(+)and (S)-(-)-2,4-dimethyl[2]paracyclo[2](5,8)quinolinophane were synthesized and employed as catalyst in the enantioselective addition of diethylzinc to aromatic aldehydes. On the basis of the ee values, ranging from 30% to 75%, and the configuration of the obtained 1-phenyl-1-propanols a plausible structure of the transition state for the alkylation process of the aldehydes is discussed.

Full text of DOI:10.1055/s-2002-25350

LETTER
747
(
S)-(–)- and (R)-(+)-4-Methyl-2-hydroxymethyl[2]paracyclo-[2](5,8)quinolino-
phane: Novel N,O-Planar Chiral Catalysts for the Enantioselective Addition of
Diethylzinc to Aldehydes
N
R
ovel N,O-Plana
e
r
Chira
l
Ca
n
talysts zo Ruzziconi,* Oriana Piermatti, Giacomo Ricci, Daniele Vinci
Dipartimento di Chimica, Università di Perugia, Via Elce di Sotto, 8, I-6100 Perugia, Italy
E-mail: ruzzchor@unipg.it
Received 31 January 2002
7
cyclophane derivatives prompted us to study the role of
the planar chirality in inducing stereoselectivity by using
a new N,O-type [2.2]paracyclophane-derived chiral cata-
Abstract: Novel planar chiral N,O-ligands derived from (R)-(+)-
and (S)-(–)-2,4-dimethyl[2]paracyclo[2](5,8)quinolinophane were
synthesized and employed as catalyst in the enantioselective addi-
tion of diethylzinc to aromatic aldehydes. On the basis of the ee val- lyst for the diethylzinc addition to aromatic aldehydes.
ues, ranging from 30% to 75%, and the configuration of the The basic idea originated from the observation that the
obtained 1-phenyl-1-propanols a plausible structure of the transition proximity of the reaction centre to the ethylene bridge of
state for the alkylation process of the aldehydes is discussed.
the [2.2]paracyclophane moiety in the transition state of a
Key words: amino-alcohols, cyclophanes, ligands, planar chirality, transition metal-catalysed reaction is crucial for the enan-
stereoselective additions, zinc
tioselection. In this respect, we found that N-acetyl- and
N-propionyl derivative of (R)-(+)-[2.2]paracyclopha-
no[4,5-d]-oxazol-2(3H)-one used as chiral auxiliary gave
Stereoselective addition of dialkylzinc reagents to alde- good enantioselectivity results in the Bu BOTf/Et N-pro-
2
3
hydes catalysed by N,O-type chiral ligands is the most moted aldol condensation with benzaldehyde. The results
common and effective method to prepare chiral secondary were explained by the steric interaction of the phenyl ring
1
2
alcohols. Since the pioneer work of Oguni and Omi,
with the ethylene bridge of the [2.2]paracyclophane moi-
many researchers have attempted this reaction, develop- ety which preclude the attack on one face of the aldehydic
ing at the same time an impressive number of chiral carbonyl group.8
ligands, mostly -aminoalcohols, by obtaining very high
In this paper we describe a simple procedure for the syn-
standard of asymmetric induction. Chiral systems belong-
ing to different chirality classes have been investigated:
central, C2-symmetric and planar chiral ligands, among
thesis of (S)-(–)- and (R)-(+)-2-hydroxymethyl-4-meth-
yl[2]paracyclo[2](5,8)quinolinophane [(S)-(–)-1 and (R)-
(
+)-1, respectively] and their use as a catalyst in the dieth-
which ferrocene-derived - and -aminoalcohols have
ylzinc addition to aromatic aldehydes. An 87% overall
yield of (S)-(+)-4-amino[2.2]paracycophane [(S)-(+)-5]
was obtained from the corresponding (S)-(+)-4-car-
boxy[2.2]paracycophane [(S)-(+)-2] by Curtius rearrange-
ment of the intermediate acylazide (S)-3 in anhydrous
toluene followed by the hydrolysis of the resulting isocy-
anate (S)-4 with 40% aqueous tetrabutylammonium hy-
droxide in tetrahydrofuran at room temperature (Scheme).
3
been the most studied systems. In some cases the planar
chirality is associated with that of a side-chain chiral car-
bon atom, so that it is very difficult to assess the contribu-
4
tion of each chirality class. Among the reported planar
chiral catalysts for stereoselective dialkylzinc addition to
carbonyl compounds, those derived from [2.2]paracyclo-
phane have received little attention, in spite of their higher
resistance to oxidation and their stability at relatively high
temperatures compared with arene and cyclopentadiene-
derived transition metal complexes. In this respect, good
stereoselectivities have been observed with a C2-symmet-
The reaction of (S)-(+)-5 with 2,4-pentanedione at
room temperature, followed by cyclisation of the result-
ing ketoimine (S)-6 in polyphosphoric acid at 75 °C, af-
forded the (S)-(–)-2,4-dimethyl[2]paracyclo[2](5,8)qui-
nolinophane [(S)-(–)-7] in 65% yield (57% overall yield
from (S)-(+)-2). Finally, the regioselective metalation of
ric bis[5-(4-hydroxy[2.2]paracyclophanyl]methane-Ti(i-
5
PrO) complex. More recently, the synthesis of N,O-type
4
chiral [2.2]paracyclophane ligands and their application
as catalyst in the dialkylzinc addition to aromatic alde-
hydes have been reported. However, once again, the pres-
ence of a chiral centre in the side-chain oxazoline N-tooth
make difficult the effective role of the planar chirality to
be assessed in determining the observed enantiomeric ex-
[
(S)-(–)-7] with butyllithium in diethyl ether, at 20 °C,9
and successive reaction with bis(trimethylsilyl)perox-
ide,10 at –75 °C, afforded (S)-(–)-1 in 79% yield (45%
1
1
overall yield from (S)-(+)-2). Starting from the enantio-
meric acid (R)-(–)-2, the corresponding quinolinophane
(R)-(+)-1 was also prepared.12
6
cess. Our experience in the synthesis of chiral [2.2]para-
(
S)-(–)-1 was employed as a catalyst for the stereoselec-
tive addition of diethylzinc to the aromatic aldehydes per-
Synlett 2002, No. 5, 03 05 2002. Article Identifier:
formed in the classical way.13
1
437-2096,E;2002,0,05,0747,0750,ftx,en;G02702ST.pdf.
Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
©

7
48
R. Ruzziconi et al.
LETTER
a
b
CH3
H
CH3
Zn O
O
COOH
CON3
NCO
N
Zn
O
N
Zn
O
Zn
(
S)-(+)-2
α]D20 = +168
c 0.5, CHCl3)
(S)-(+)-3
(S)-4
H
si face
[
c
re face
(
11a
11b
O
e
d
Figure
N
N
NH2
(
S)-(-)-7
(S)-6
(S)-(+)-5
[α]D20 = +83
zinc atom is probably responsible for the enantioselectiv-
ity of the process. Semi-empiric calculations show that
transition state 11a is about 0.9 kcal/mol more stable than
[
α]D20 = -38
(
c 0.52, CHCl3)
(c 0.58, CHCl3)
f
1
1b, which is compatible with the observed ee values. Ac-
cording to the most reliable pattern now accepted for this
1c
kind of processes, the ethyl group of a second molecule
of diethylzinc in 11a attacks the re face of the carbonyl
group to give the (R)-(+)-1-aryl-1-propanol as the main
enantiomer.
N
OH
Although the enantioselectivities observed with this
ligand are far from the standard achieved with other chiral
-aminoalcohols, the present work is one of the few ex-
amples of an N,O-type catalyst for the enantioselective
alkylation of aromatic aldehydes exhibiting pure planar
chirality.
(
S)-(-)-1
α]D20 = -16
[
(
c 0.50, CHCl3)
Scheme a) SOCl , NaN , acetone/H O, r.t.; b) Toluene reflux, 97%
from (S)-(+)-2; c) 50% aq Bu NOH, THF, r.t., 90%; d) acetylacetone,
r. t. 2 h; e) (H PO ) , 75 °C, 48 h, 65% from (S)-(+)-5; f) BuLi, Et O,
40 °C, (Me SiO) , H O , 79% from (S)-(–)-7, 45% from (S)-(+)-2.
2
3
2
4
3
4 n
2
+
–
A planar-chiral heterocyclic ligand that is structurally
similar to (S)-(–)-1, but belonging to the ferrocene series,
was used by Fu in the diethylzinc addition to benzalde-
3
2
3
1
5
hyde. With this catalyst too, modest enantioselectivities
were observed (ee 51%). No mechanistic hypothesis was
advanced to account for the (S)-configuration of the main
enantiomer obtained with (R)-(–)-ligand, although the
same mechanism suggested for the reaction with (S)-(–)-1
could be invoked. Other homocyclic ferrocene-derived -
amino-alcohols exhibiting pure planar chirality gave un-
satisfactory ee values. The poor enantioselectivity found
with this class of catalyst can most probably be imputed to
the small differences between the conformational stabili-
ties of the transition states like 11a and 11b. Pure planar
chirality, at least in this type of ligand, does not seem to
allow a high standard of enantioselectivity, unless sub-
stantial modification are made in the OH-bringing side-
chain.15
Reaction of diethylzinc with the aldehydes 8a–h in the
presence of (S)-(–)-1 (0.1 equiv) in toluene at 20 °C af-
forded (+)-(R)-1-aryl-1-propanols 9a–h in good yields
with the ee ranging from 30 to 75%. Results are reported
in the Table.
An increase of enantioselectivity was observed when the
Et Zn/aldehyde molar ratio was increased, the optimal
2
one being 5:1. This in accord with the finding of Noyori
regarding the presence of different catalytic species in
equilibrium in solution, the most effective one predomi-
nating at the highest concentration of diethylzinc.14 The
low temperatures bias both the yield and the enantioselec-
tivity, while the reaction time increases considerably
favouring the competing reduction of the aldehyde to ben-
zylic alcohol (10). The absolute R configuration of the
main enantiomer observed for all the 1-aryl-1-propanols
and similar values of the optical rotation suggest a transi-
tion state structure for the transfer of the ethyl from zinc
to the formyl group as depicted below (Figure).
16
Work aimed at increasing the performance of this catalyst
by structural changes in the side-chain hydroxymethyl, as
well as in the dialkylzinc reagent, is currently in progress.
Coordination of the carbonyl oxygen on the zinc atom of Acknowledgement
the catalytic species formed by reaction of (S)-(–)-1 with
This work was carried out within the framework of COST Action
D12. Thanks are due to the Ministero dell’Università e della Ricerca
O heterocyclic ring (Figure). The steric interaction be- Scientifica e Tecnologica (MURST) and to the University of Peru-
tween the aldehydic hydrogen and the ethyl group on the gia (COFIN 2001, contract n. 2001038157) for financial support.
diethyl zinc occurs at the less hindered side of the N-Zn-
Synlett 2002, No. 5, 747–750 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Novel N,O-Planar Chiral Catalysts
749
Table Reaction of Diethylzinc with Aldehydes 8a–h catalysed by (S)-(–)-1 and (R)-(+)-1 (0.1 equiv) in toluene at 20 °C
OH OH
O
(
S)-(-)-1 (0.1 eq.)
H
Y
+ Zn(CH CH )
Y
+
Y
2
3 2
Toluene, 20 °C
8a-h
9a-h
10a-h
a
Aldehyde
-Naphthaldehyde (8a)
Catalyst, (10%)
t (h)
Yield 9a–h (%)
10a–h (%)
ee (Config.)
b
2
[(S)-( )-1]
14
110
21
93
33
74
97
7
50
10
3
66 (R)
61 (R)
46 (S)
c
[
[
[
(S)-( )-1]
(R)-(+)-1]
(S)-( )-1]
d
14
75 (R)
64 (R)
70 (R)e
62 (R)
66 (R)
61 (R)
30 (S)
42 (R)
Benzaldehyde (8b)
[(S)-( )-1]
[(S)-( )-1]
[(S)-( )-1]
[(S)-( )-1]
[(S)-( )-1]
[(R)-(+)-1]
[(S)-( )-1]
5
5
99
93
1
1
4
3
3
4
3
-(Trifluoromethyl)benzaldehyde (8c)
,5-Bis(trifluoromethyl)benzaldehyde (8d)
-Anisaldehyde (8e)
3
95
1
8
85
6
-Anisaldehyde (8f)
17
3
86
5
-Pyridinecarboxaldehyde (8g)
100
98
–
Cinnamaldehyde (8h)
3
2
a
Determined by HPLC analysis of the crude reaction mixture on a DAICEL OD-H column using mixtures of hexane/isopropanol as the eluent.
b
c
d
e
A 2:1 Et Zn/aldehyde molar ratio was used.
2
Reaction performed at 0 °C.
0
.02 Equiv of catalyst was employed.
Determined by HPLC analysis of the corresponding acetate on a DAICEL OJ column using hexane as the eluent.
References
(8) Fringuelli, F.; Piermatti, O.; Pizzo, F.; Ruzziconi, R. Chem.
Lett. 2000, 38.
(
1) (a) Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757. (b) Soai,
K.; Niwa, S. Chem. Rev. 1992, 92, 833. (c) Noyori, R.;
Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 49.
2) (a) Oguni, N.; Omi, T. Tetrahedron Lett. 1984, 25, 2823.
(
9) Kaiser, E. M.; Bartling, G. J.; Thomas, W. R.; Nochols, S.
B.; Nash, D. R. J. Org. Chem. 1973, 38, 71.
10) Ricci, A.; Taddei, M. Synthesis 1986, 633.
(
(
(
11) (S)-(–)-1 [45% from (S)-(+)-2]. Mp 116–118 °C (from
(
b) Oguni, N.; Omi, T.; Yamamoto, Y.; Nakamura, A. Chem.
20
1
diethyl ether). [ ]D –16.0 (c 0.50, CHCl ). H NMR
3
Lett. 1983, 841.
(
CDCl , 400 MHz): = 6.93 (s, 1 H), 6.90 (d, J = 7.3 Hz, 1
3
(
(
3) Dosa, P. I.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1997, 62,
H), 6.80 (d, J = 7.3 Hz, 1 H), 6.46 (s, 2 H), 5.72 (d, J = 7.8
Hz, 1 H), 5.46 (d, J = 7.8 Hz, 1 H), 4.93–4.80 (four peaks,
AB system, J = 15.0 Hz, 2 H), 4.88 (br s, 1 H), 4.28–4.25 (m,
4
44.
4) (a) Watanabe, M.; Araki, S.; Butsugan, Y. J. Org. Chem.
991, 56, 2218. (b) Uemura, M.; Miyake, R.; Nakayama, K.;
Shiro, M.; Hayashi, Y. J. Org. Chem. 1993, 58, 1238.
c) Malfait, S.; Pélinski, L.; Brocard, J. Tetrahedron:
1
1
2
H), 3.84 (dd, J = 14.0 and 9.2 Hz, 1 H), 3.19–2.92 (m, 5 H),
13
.68 (s, 3 H), 2.61–2.50 (m, 1 H). C NMR (CDCl , 100
3
(
MHz): = 155.0, 148.4, 144.3, 139.4, 138.8, 137.8, 137.3,
Asymmetry 1998, 9, 2595. (d) Malézieux, B.; Andrés, R.;
Gruselle, M.; Rager, M.-N.; Thorimbert, S. Tetrahedron:
Asymmetry 1999, 10, 3253. (e) Bolm, C.; Muñiz-Fernández,
K.; Seger, A.; Raabe, G.; Günther, K. J. Org. Chem. 1998,
1
33.7, 132.8, 132.5, 131.3, 129.6, 128.2, 127.8, 119.8, 63.4,
–1
37.6, 35.2, 34.4, 31.9, 22.8. IR: (CHCl ) 3417 cm (broad,
3
OH). Anal. Calcd for C H NO: C, 83.13; H, 6.98; N, 4.62.
2
1
21
Found: C, 83.20; H, 6.99; N, 4.54.
63, 7860.
(
12) Chiral [2]paracyclo[2](5,8)quinolinophane and some
derivatives were first isolated from semi-preparative chiral
HPLC of the racemic mixture in turn obtained in poor
overall yield by condensation of 5,8-bis(bromo-
(
(
(
5) Rozenberg, V. I.; Antonov, D. Y.; Zhuravsky, R. P.;
Vorontsov, E. V.; Khrustalev, V. N.; Ikonnikov, N. S.;
Belokon, Y. N. Tetrahedron: Asymmetry 2000, 11, 2683.
6) (a) Dahmen, S.; Bräse, S. Chem. Commun. 2002, 26.
methyl)quinolines with 1,4-bis(mercaptomethyl)benzene
followed by sulphur extrusion. CD spectra of the resolved
enantiomers were reported without configuration assigne-
ment: Wörsdörfer, U.; Vögtle, F.; Glorius, F.; Pfaltz, A.
J. Prakt. Chem. 1999, 341, 445.
(
b) Wu, X.-W.; Hou, X.-L.; Dai, L.-X.; Tao, J.; Cao, B.-X.;
Sun, J. Tetrahedron: Asymmetry 2001, 12, 529.
7) (a) Cipiciani, A.; Fringuelli, F.; Mancini, V.; Piermatti, O.;
Pizzo, F.; Ruzziconi, R. J. Org. Chem. 1997, 62, 3744.
(
b) Cipiciani, A.; Fringuelli, F.; Mancini Piermatti, O. F.;
Scappini, A. M.; Ruzziconi, R. Tetrahedron 1997, 53,
1853. (c) Rosini, C.; Ruzziconi, R.; Superchi, S.;
Fringuelli, F.; Piermatti, O. Tetrahedron: Asymmetry 1998,
, 55.
(
13) Typical Procedure. Diethylzinc (3.3 mL, 0.1 M in toluene,
3.3 mmol) was added by a syringe to a solution of [(S)-(–)-
1
1] (20 mg, 0.066 mmol) in dry toluene (3 mL) under nitrogen
at 20 °C and the mixture was allowed to react for 20 min.
The aldehyde (0.66 mmol) was added and the mixture was
9
Synlett 2002, No. 5, 747–750 ISSN 0936-5214 © Thieme Stuttgart · New York

7
50
R. Ruzziconi et al.
LETTER
made to react at 20 °C until it completely disappeared
or their derivatives on different chiral columns depending on
the structure of the alcohol by using hexane/isopropanol
mixtures as the eluent.
(
monitored by GLC). Sat. aq NH Cl was added (10 mL) and
4
the mixture was extracted with diethyl ether (3 20 mL).
The collected organic phases were washed with water, dried
over Na SO and the solvent was evaporated. Preparative
(14) Kitamura, M.; Okada, S.; Surga, S.; Noyori, R. J. Am. Chem.
Soc. 1989, 111, 4028.
2
4
TLC on silica gel (eluent, petroleum ether/diethyl ether
mixtures) allowed the corresponding 1-aryl-1-propanols to
be isolated. The ee was determined by HPLC of the alcohols
(15) Dosa, P. I.; Ruble, J. G.; Fu, G. J. Org. Chem. 1997, 62, 444.
(16) Nicolosi, G.; Patti, A.; Morrone, R.; Piattelli, M.
Tetrahedron: Asymmetry 1994, 5, 1642.
Synlett 2002, No. 5, 747–750 ISSN 0936-5214 © Thieme Stuttgart · New York