Enantioselective Addition of Diethylzinc to Aldehydes Catalyzed by a Titanate Complex with a Chiral Tetradentate Ligand

Full text of DOI:10.1021/jo970055s

J . Org. Chem. 1997, 62, 2665-2668
2665
En a n tioselective Ad d ition of Dieth ylzin c to
Ald eh yd es Ca ta lyzed by a Tita n a te
Com p lex w ith a Ch ir a l Tetr a d en ta te
Liga n d
J un Qiu, Cheng Guo, and Xumu Zhang*
Department of Chemistry, The Pennsylvania State
University, University Park, Pennsylvania 16802
Received J anuary 9, 1997
The addition of dialkylzincs to aldehydes is one of the
most widely studied carbon-carbon bond-forming reac-
tions. Many systems reported to date use amino alcohols
as ligands and zinc complexes as catalysts.1 The asym-
metric version of this alkylation reaction can also be
catalyzed by chiral titanate complexes2-4 (e.g., TAD-
DOLs2 and chiral sulfonamides3). We have recently
studied a titanate complex with tetradentate helical
ligand 1 ((1R,2R)-(+)-1,2-bis(3,5-dichloro-2-hydroxyben-
zenesulfonamido)cyclohexane) for the asymmetric addi-
tion of diethylzinc to aldehydes (Figure 1).5 Herein we
report the scope of this enantioselective reaction with
various substrates. This alkylation approach provides
a useful route for the synthesis of some chiral secondary
alcohols, especially allylic alcohols,6 and this work con-
tributes to an understanding of the details of this type
of reaction.
F igu r e 1.
F igu r e 2.
Resu lts a n d Discu ssion
Using phenolic aromatic sulfonamide 1 as the key cleft-
defining group can potentially provide an excellent steric
(1) For recent reviews: (a) Noyori, R.; Kitamura, M. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 49. (b) Soai, K.; Seiji, S. Chem. Rev. 1992, 92,
833.
(2) For TADDOLs as ligands: (a) Schmidt, B.; Seebach, D. Angew.
Chem., Int. Ed. Engl. 1991, 30, 99. (b) Seebach, D.; Behrendt, L.; Felix,
D. Angew. Chem., Int. Ed. Engl. 1991, 30, 1008. (c) Schmidt, B.;
Seebach, D. Angew. Chem., Int. Ed. Engl. 1991, 30, 1321. (d) von dem
Bussche-Hunnefeld, J . L.; Seebach, D. Tetrahedron 1992, 48, 5719.
(e) Seebach, D.; Plattner, D. A.; Beck, A. K.; Wang, Y. M.; Hunziker,
D.; Petter, W. Helv. Chim. Acta 1992, 75, 2171. (f) Seebach, D.; Beck,
A. K.; Schimdt, B.; Wang, Y. M. Tetrahedron 1994, 50, 2171. (g) Weber,
B.; Seebach, D. Tetrahedron 1994, 50, 7473. (h) Ito, Y. N.; Ariza, X.;
Beck, A. K.; Boha´c, A.; Granter, C.; Gawley, R. E.; Ku¨hnle, F. N. M.;
Tuleja, J .; Wang, Y. M.; Seebach, D. Helv. Chim. Acta 1994, 77, 2071.
(3) For disulfonamides as ligands: (a) Takahashi, H.; Kawakita, T.;
Yoshioka, M.; Kobayashi, S.; Ohno, M. Tetrahedron Lett. 1989, 30,
7095. (b) Yoshioka, M.; Kawakita, T.; Ohno, M. Tetrahedron Lett. 1989,
30, 1657. (c) Takahashi, H.; Kawakita, T.; Ohno, M.; Yoshioka, M.;
Kobayashi. S. Tetrahedron 1992, 48, 5691.
(4) For more disulfonamides and related ligands: (a) Rozema, M.
J .; AchyuthaRao, S.; Knochel, P. J . Org. Chem. 1992, 57, 1956. (b)
Brieden, W.; Ostwald, R.; Knochel, P. Angew. Chem., Int. Ed. Engl.
1993, 32, 582. (c) Rozema, M. J .; Eisenberg, C.; Lutjens, H.; Ostwald,
R.; Belyk, K.; Knochel, P. Tetrahedron Lett. 1993, 34, 3115. (d)
Nowotny, S.; Vettel, S.; Knochel, P. Tetrahedron Lett. 1994, 35, 4539.
(e) Schwink, L.; Knochel, P. Tetrahedron Lett. 1994, 35, 9007. (f)
Lutjens, H.; Knochel, P. Tetrahedron: Asymmetry 1994, 5, 1161. (g)
Ostwald, R.; Chavant, P.-Y.; Stadtmuller, H.; Knochel, P. J . Org. Chem.
1994, 59, 4143. (h) Lutjens, H.; Nowotny, S.; Knochel, P. Tetrahe-
dron: Asymmetry 1995, 6, 2675. (i) Berninger, J .; Koert, U.; Eisenberg-
Ho¨hl, C.; Knochel, P. Chem. Ber. 1995, 128, 1021. (j) Vettel, S.; Lutz,
C.; Knochel, P. Synlett 1996, 731. (k) Langer, F.; Schwink, L.;
Devasagayaraj, A.; Chavant, P.-Y.; Knochel, P. J . Org. Chem. 1996,
61, 8229. (l) Ito, K.; Kimura, Y.; Okamura, H.; Katsuki, T. Synlett 1992,
573. (m) Soai, K.; Hirose, Y.; Ohno, Y. Tetrahedron: Asymmetry 1993,
4, 1473. (n) Dreisbach, C.; Kragl, U.; Wandrey, C. Synthesis 1994, 911.
(o) Waldman, H.; Weigerding, M.; Dreisbach, C.; Wandrey, C. Helv.
Chim. Acta 1994, 77, 2111.
F igu r e 3.
environment to influence the orientation of substrates.
Table 1 summarizes the experimental results of asym-
metric addition of diethylzinc to various aldehydes. In
general, highly enantioselective additions have been
realized.
There have been several different mechanisms pro-
posed for the addition of diethylzinc to aldehydes. We
have examined the nature of the titanate complex 2 in
the catalytic addition of diethylzinc to aldehydes by NMR
spectroscopy and nonlinear asymmetric induction effect.5
The experimental data suggested that the catalyst con-
taining ligand 1 is a monomeric titanate species during
the asymmetric bond forming process. On the basis of
our investigation and related mechanistic studies by
Seebach,2 Yoshioka,3 and Knochel,4a-k a plausible key
intermediate is the bimetallic complex 3, which has the
dialkylzinc coordinated to the two phenoxide groups prior
to the transfer of the ethyl group to the carbonyl (Figure
2). The excess Ti(OPri)4 removes the zinc alkoxide from
the titanium center.2 The removal of zinc alkoxide has
to be efficient or the catalytic cycle will not continue. This
alkylation reaction is a typical ligand-accelerated cata-
lytic process,7 in which the titanate complex 2 is a better
catalyst than Ti(OPri)4 alone.
(5) (a) Zhang, X.; Guo C. Tetrahedron Lett. 1995, 36, 4947. (b) Guo,
C.; Qiu, J .; Zhang, X.; Verdugo, D.; Larter, M. L.; Christie, R.; Kenney,
P.; Walsh, P. L. Tetrahedron, in press.
(6) Other synthetic methods of chiral allylic alcohols: (a) Martin,
V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda, Y.; Sharpless,
K. B. J . Am. Chem. Soc. 1981, 103, 6237. (b) Kitamura, M.; Kasahara,
I.; Manabe, K.; Noyori, R.; Takaya, H. J . Org. Chem. 1988, 53, 708.
(7) Berrisford, D. J .; Bolm, C.; Sharpless, K. B. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1059.
S0022-3263(97)00055-8 CCC: $14.00 © 1997 American Chemical Society

2666 J . Org. Chem., Vol. 62, No. 8, 1997
Ta ble 1. En a n tioselective Ad d ition of Et2Zn to Ald eh yd es Ca ta lyzed by th e Tita n a te Com p lex of 1
Notes
a
b
Determined by HPLC using a CHIRALCEL OD column, by GC using a â-DEX column, or by 1H NMR of its Mosher ester. Isolated
yield.
On the basis of this model, the enantioselectivity is set
the reaction, one of the axial positions is occupied by an
aldehyde. The Lewis acidity of the titanium center
activates the substrate and accelerates the reaction. The
two benzene rings from the ligand generate a chiral
environment which limits the free rotation of the sub-
when the ethyl group is transferred intramolecularly
from zinc to the carbonyl carbon. In the bimetallic
complex 2, the “wall” formed by the two benzene rings is
suitable to control enantioselectivity (Figure 3). During

Notes
J . Org. Chem., Vol. 62, No. 8, 1997 2667
F igu r e 4. Rationale for asymmetric alkylation of aldehydes.
strates; thus, the Re and Si faces of benzaldehyde are
differentiated (Figure 3). The orientation of benzalde-
hyde is well controlled with ligand 1, and the ethyl group
can be transferred only to the Si face of the substrate.
The disfavored interaction between the rigid wall and the
aromatic ring of benzaldehyde makes it disfavored for
the ethyl group to be transferred to the Re face (entry 1
in Table 1).
obtained with some substituted alkyl aldehydes (entries
20-23). Unbranched aliphatic aldehydes give a low ee
(entry 24). The energy difference of the favored and
disfavored geometry with linear aliphatic aldehydes is
not significant in case D.
Our ligand system is similar to Yoshioka’s chiral
disulfonamides. Yoshioka’s3 and Knochel’s4a-k study
revealed a similar trend of enantioselectivity in dieth-
ylzinc addition to aromatic aldehydes, conjugated alde-
hydes with or without R-substitution, and aliphatic
aldehydes. For conjugated aldehydes, R-substitution
leads to higher ee and â-substitution leads to lower ee
with both catalytic systems.4c However, the change in
enantioselectivity is larger in our ligand system. This
difference may be due to the nature of the titanate
complex coordinated by the rigid tetradentate chelating
ligand 1, which cannot adjust its geometry to fit different
substrates. Thus, a small change in the substrate
structure can lead to a big difference in the enantiose-
lectivity.
Using this notion, we have developed a rationale to
explain our experimental results (Figure 4). High enan-
tioselectivity was observed with aromatic aldehydes (case
A, Figure 4) (>90% ee, entries 1-3, 5, 7-8, and 10-11).
Introduction of functional groups in the ortho position of
aromatic aldehydes decreases enantioselectivity (entry
4 vs entry 5; entry 6 vs entry 7; entry 9 vs entry 8). One
plausible explanation of this observation is that the ortho
functional groups can chelate the titanium center and
change the transition state geometry (e.g., octahedron).
For example, a methoxyl group has a stronger coordinat-
ing ability than chloride, which results in a bigger drop
in enantioselectivity. In particular, the opposite enan-
tioselectivity was observed when 2-methoxyl-1-naphthyl
aldehyde was used as the substrate instead of 1-naphthyl
aldehyde. On the other hand, an ortho methyl group in
the aromatic aldehydes cannot participate in this chela-
tion and high enantioselectivity was obtained (entry 2).
Analogous to aromatic aldehydes (case A), conjugated
aldehydes with R-substitution have the preferred Si
orientation for the addition of ethyl group (case B). High
ee’s were observed with this type of substrate (entries
12-16). Substitution of hydrogen with an alkyl group
in the â position decreases the enantioselectivity (entry
17 vs entry 12). A more dramatic change in the enan-
tioselectivity of addition was demonstrated by removing
the R-substituent in the conjugated aldehydes (entry 17
vs entry 18; entry 15 vs entry 20). This decrease may
result from the fact that the two orientations of conju-
gated aldehydes without R-substitution have very little
energy difference as illustrated in case C in Figure 4.
The worst substrate of this family is the one with two
â-substituents and without R-substitution (entry 19).
High enantioselectivity is generally more difficult to
achieve with aliphatic aldehydes than with aromatic
aldehydes.1 However, good to excellent ee’s can be
Con clu sion
A variety of aldehydes have been examined as sub-
strates for Ti-catalyzed enantioselective addition of Et2-
Zn in the presence of 1. High enantioselectivity was
obtained with aromatic aldehydes, conjugated aldehydes
with R-substitution, and some substituted aliphatic al-
dehydes. Introduction of ortho chelating groups with
aromatic aldehydes and removal of R-substituent in
conjugated aldehydes decreases enantioselectivity. Lin-
ear aliphatic aldehydes are poor substrates for this
alkylation reaction. A working model was used to explain
this observation. Several useful chiral secondary alcohols
can be obtained using this methodology.
Exp er im en ta l Section
Gen er a l In for m a tion . Unless otherwise indicated, all reac-
tions were carried out under nitrogen. Hexane were freshly
distilled from CaH2. Reactions were monitored by thin-layer
chromatographic (TLC) analysis. Column chromatography was
performed using EM silica gel 60 (230-400 mesh). Diethylzinc
(1.0 M in hexane) was available from Aldrich Co. and used
directly. Titanium(IV) isopropoxide was stored under nitrogen.
Aldehydes were distilled before use.

2668 J . Org. Chem., Vol. 62, No. 8, 1997
Notes
1H NMR spectra were recorded on 200, 300, or 360 MHz
spectrometers. Chemical shifts are reported in ppm downfield
from TMS with the solvent resonance as the internal standard
(CDCl3, δ 7.26 ppm). 13C NMR spectra were recorded with
complete proton decoupling. Chemical shifts are reported in
ppm downfield from TMS with the solvent resonance as the
internal standard (CDCl3, δ 77.0 ppm). GC analysis were carried
on a Helwett-Packard 5890 gas chromatograph with a 30-m
Supelco â-DEX column. HPLC analyses were carried out on a
Waters 600 chromatograph with a 25-cm CHIRALCEL OD
column.
Exp er im en ta l P r oced u r e for En a n tioselective Ad d ition
of Et2Zn to a n Ald eh yd e. Chiral ligand 1 (0.20 mmol) was
added to dry hexane (50 mL), and titanium(IV) isopropoxide
(0.42 mL, 1.4 mmol) was added under N2. The mixture was
heated at reflux for 1 h. After the flask was cooled to -23 °C,
the diethylzinc (1.8 mmol) was added followed by the aldehyde
(1.0 mmol). Stirring was continued at -23 °C for 4 h. HCl (1
M, 10 mL) was added, and the mixture was extracted with ether
(3 × 20 mL). The combined organic layers were dried over Na2-
SO4 and concentrated. The crude product was passed through
a silica gel column (eluting with CH2Cl2), and the enantioselec-
tivity of the product was measured by HPLC or GC with chiral
columns.
Ack n ow led gm en t. This work was supported by a
Camille and Henry Dreyfus New Faculty Award, The
Petroleum Research Fund of the American Chemical
Society, a DuPont Young Faculty Award, and the
Hoechst Celanese Corporation. X.Z. thanks Supelco for
the gift of a â-DEX GC column.
Su p p or tin g In for m a tion Ava ila ble: Detailed conditions
for the analysis of chiral secondary alcohols (2 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
J O970055S