Titanium 3,3′-modified-biphenolate complexes atropisomerically controlled by TADDOLs: Novel chiral Lewis acid catalysts for asymmetric methylation with an achiral methyl-titanium reagent

Article abstract of DOI:10.1055/s-2001-18770

Chiral Ti complexes, which are constituted of 3,3′-modified-biphenolate (BIPOLate) ligands atropisomerically controlled by (R)-TADDOLs, are shown to be novel chiral Lewis acid catalysts for the methylation reaction of aldehydes with an achiral methyl-tita

Full text of DOI:10.1055/s-2001-18770

LETTER
1889
Titanium 3,3’-Modified-Biphenolate Complexes Atropisomerically Controlled
by TADDOLs: Novel Chiral Lewis Acid Catalysts for Asymmetric
Methylation with an Achiral Methyl-Titanium Reagent
T
M
itanium 3, 3’-Modifie
a
k
C
omplex
o
Department of Applied Chemistry, Tokyo Institute of Technology O-okayama, Meguro-ku, Tokyo 152-8552, Japan
Fax +81(3)57342776; E-mail: kmikami@o.cc.titech.ac.jp
Received 26 July 2001
process of an achiral reagent or catalyst to provide an ac-
tivated but achiral one.
Abstract: Chiral Ti complexes, which are constituted of 3,3’-mod-
ified-biphenolate (BIPOLate) ligands atropisomerically controlled
5
by (R)-TADDOLs, are shown to be novel chiral Lewis acid cata- In order to obtain the enantiopure forms of atropos, for
lysts for the methylation reaction of aldehydes with an achiral me-
example binaphthol (BINOL), ligands, asymmetric syn-
thyl-titanium reagent. Thus, the chiral 3,3’-modified BIPOLate/
TADDOLate-Ti complexes give enhanced enantioselectivities up
to 100% enantiomeric excess.
5
thesis or resolution is required. By contrast, the tropos bi-
phenol (BIPOL) counterparts (Figure 2) can, in principle,
be used without their asymmetric synthesis or resolution,
because they can be controlled in enantio-enriched forms,
after complexation with a chiral activator 1) to control the
chirality through epimerization and 2) to increase the cat-
alyst activity of the complex („asymmetric activation“).4
Key words: asymmetric methylation, atropisomer, chiral Lewis
acid catalyst, chiral titanium complex, 3,3’-modified biphenols
Development of an asymmetric catalyst is of central im-
portance in modern synthetic and pharmaceutical chemis-
1
try, wherein the design of a chiral ligand is the key to
HO
OH
increase the catalyst activity from an achiral pre-catalyst
and, hence, to induce chirality in a product („ligand accel-
2
HO
OH
erated catalysis“ ). In homogeneous asymmetric catalysis,
Sharpless et al. have emphasized the significance of
„
chiral ligand acceleration“. An asymmetric catalyst is
formed from an achiral „pre-catalyst“ via ligand exchange
with an added chiral ligand (Figure 1). In heterogeneous
asymmetric catalysis, the term „chiral modification“ is
BIPOL : Tropos
BINOL : Atropos
3
coined for the process of modifying an achiral heteroge- Figure 2 Tropos or Atropos
neous catalyst, particularly on the surface with a „chiral
modifier“, namely a „chiral ligand“ (Figure 1). The asym-
However, in an ene reaction, we have already examined a
metric catalysts thus prepared can be further evolved into
highly activated catalysts by association with chiral acti-
combination of BIPOLate-Ti complex with atropos
BINOL to control the chirality of the tropos BIPOL ligand
and to increase the catalytic activity of the BIPOLate-Ti
complex but eventually observed a ligand exchange reac-
4
vators (Figure 1). The term „asymmetric activation“ may
be proposed for this process in an analogy to the activation
6
tion of BIPOL with BINOL (Scheme 1). Furthermore,
we have reported that TADDOLate-Ti complexes exhibit
a higher catalytic activity and enatioselectivity through
asymmetric activation with BINOL (Scheme 2). There-
7
Asymmetric Activation
Chiral
Chiral
Active
Act*
fore, we examine the Lewis acid catalysis by a titanium
complex (1) consisting of tropos and sterically demanding
BIPOL with substituents at the 3,3’-position in a combi-
nation of TADDOLs to control the chirality of the BIPOL
ligand (Scheme 3) in the methylation reaction with achiral
methyl-titanium complex as a nucleophilic and sterically
demanding methylating reagent. Herein, we report that
the dynamic chirality control of the BIPOL ligands gives
highly enantiomerically pure methylcarbinols of great
synthetic use by the molecular design of 3,3’-substituted
BIPOL.
Act*
Highly activated
Chiral activator
"
Chiral ligand acceleration" ("Chiral modification")
"
Activation"
Achiral
Achiral
Active
Less active
Figure 1 Asymmetric activation
Synlett 2001, No. 12, 30 11 2001. Article Identifier:
437-2096,E;2001,0,12,1889,1892,ftx,en;Y14501ST.pdf.
Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
1
©

1
890
M. Ueki et al.
LETTER
The BIPOLate/TADDOLate-Ti catalysts (1) were pre-
i
pared in the following manner: Treatment of Ti(O Pr) and
4
H
O
O
i
i
O
O
OPr
(R)-BIPOL in toluene for 1 hour gave Ti(O Pr) (BIPOLa-
to) . Ti(O Pr) (BIPOLato) was, upon addition of TAD-
O
O
2
Ti
+ BINOL
Ti
i
6
i
OPr
O
H
2 2 2
O
DOL, found to be transformed to Ti(BIPOLato)
TADDOLato) (1).
(
Ti-BIPOLato
We have thus examined the methylation reaction with
achiral methyltitanium triisopropoxide. It is generally dif-
ficult to carry out these methylation reactions in a catalyt-
ic manner, because of the high nucleophilicity of the
achiral methylation reagent. In this paradox, however,
these reactions were found to be catalyzed effectively by
the use of only 10 mol% of the titanium catalysts (1) to
give the methylcarbinol in good isolated yields but in
moderate enantioselectivities at –78 to –35 °C (Table 1).
Scheme 1
Ar
O
Ar
O
Ar
Ar
Ar
i
O Pr
O
O
O
O
O
Ti
+ BINOL
Ti
i
O
OPr
O
O
Ar
Ar
Ar
Ti-TADDOLato
Table 1 Catalysis by BINOLate/TADDOLate-Ti Complex 1aa
Scheme 2
Entry
Temp (°C)
Yield (%)
Enantioselectivity
% ee)
(
R2
R1
R2
R1
1
2
3
0
79
60
18
45
73
66
Ar
Ar
Ar
i
O
O
O
O
O
OPr
O
O
–70 to –35
–70 to –35
+
TADDOL
Ti
Ti
i
OPr
O
Ar
R2
R1
R2
R1
a
1
2
Catalyzed by 3 mol% of 1a (R =R =H)
(
1)
Scheme 3
We have thus designed modified BIPOLate/TADDOLa-
te-Ti complexes by the introduction of sterically demand-
ing substituents at the 3,3’-positions, which closely locate
toward the chiral TADDOLate ligands (Table 2). Prepara-
tion of the 3,3’-substituted BIPOLs is as follows: Com-
mercially available BIPOL was transformed to bromide 2
In catalytic asymmetric carbon-carbon bond forming re-
actions, highly promising candidates for the asymmetric
catalysts are Lewis acidic metal complexes bearing chiral
and non-racemic ligands. For example, catalytic asym-
metric alkylation with diethylzinc reagent has been suc-
cessfully reported, using chiral aminoalcohol–zinc
8
9
with sec-Bu NH and Br . The Suzuki coupling of 2 with
2
2
2
phenylboronic acid afforded 3,3’-diphenyl BIPOLs 3b,c
Scheme 5). 3,3’-Dimethyl BIPOL 3d was prepared by
9
10
11
12
catalysts by Oguni, Soai, Noyori, and Knochel. In
sharp contrast, only low levels of enantioselectivity (up to
(
methylation. 3,3’-Dimethoxy BIPOL 3e was prepared by
oxidative coupling with CuCl(OH)/TMEDA.
1
3
5
9% ee) were obtained in the methylation reaction with
dimethylzinc even by using similar aminoalcohol–zinc
catalysts (Scheme 4), presumably because of low steric
demand of dimethylzinc reagent. Thus, we developed
chiral BIPOLate/TADDOLate-Ti catalysts (1) to give en-
hanced enantioselectivities up to 100% ee, in a combina-
tion with a highly nucleophilic but sterically demanding
achiral methyl-titanium reagent.
As expected, the introduction of sterically bulky 3,3’-sub-
stituents leads to the increase in enantioselectivity except
for the phenylated ones (1b and 1c) (Table 2). Particular-
ly, 3,3’-dimethoxy derivative (1e) gave virtually complete
enantioselectivity (100% ee) in sharp contrast to the mod-
Table 2 3,3'-Modified BIPOLate/TADDOLate-Ti Complexes 1a
1
R1
R2
Yield (%)
Enantioselec-
tivity (% ee)
OH
CHO
1
i
+
MeTi(OPr)3
1b
1c
Ph
H
H
36
40
69
65
F3C
CF3
F3C
CF3
OMe
Ph
HO
cf. Me2Zn (3 eq)
59% ee (Ref. 13)
1d
Me
H
56
60
88
N
1
e
MeO
Me
100
Scheme 4
a
Conditions: toluene, 12 hours, –78 to –35 °C.
Synlett 2001, No. 12, 1889–1892 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Titanium 3,3’-Modified-Biphenolate Complexes as Catalysts
1891
MeO
1
) NaH, MeI
MeO
Ph
Ph
O
Ph
Ph
Ph
2
) tBuLi
O
O
OH
OH
O
O
O
O
O
O
O
Ti
Ti
O
3
) MeI
O
4
) BBr3
Ph
Ph
Ph
MeO
(R, R)
36.93 kcal/mol
MeO
3d
Br
(R, S)
Br2
sBuNH2
-
-33.33 kcal/mol
OH
OH
OH
OH
Figure 3 MM2 Calculation
toluene
78 °C - -30 °C
-
Br
2
BIPOL
1
R B(OH)2
R1
Pd(PPh3)4
K3PO4
OH
OH
dioxane
60 °C
R1
3
b: R1 = Ph
MeO
c: R1=
OMe
OMe CuCl(OH) / TMEDA
OH
OH
Figure 4 Si- vs. Re-Face Approach (CF3 have been omitted for cla-
rity)
CH2Cl2
OH
OMe
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Synlett 2001, No. 12, 1889–1892 ISSN 0936-5214 © Thieme Stuttgart · New York