Tetrahedron Letters
Vasicine as tridentate ligand for enantioselective addition
q
of diethylzinc to aldehydes
a
a
a
b
a,
⇑
Mushtaq A. Aga , Brijesh Kumar , Abdul Rouf , Bhahwal A. Shah , Subhash C. Taneja
a
Bio-Organic Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, J&K, India
Natural Product Microbes, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, J&K, India
b
a r t i c l e i n f o
a b s t r a c t
Article history:
The first report of natural L-vasicine as tridentate chiral ligand for the enantioselective addition of dieth-
Received 20 January 2014
Revised 1 March 2014
Accepted 2 March 2014
Available online 11 March 2014
ylzinc to a variety of aliphatic and aromatic aldehydes is described. The ligand generates R-isomer of the
secondary alcohols upto 98% ee. The quinazoline structure possibly imparts rigidity to the ligand and
hence, consistently high enantioselectivity. The importance of the quinazoline ring was also supported
by the reaction with other related ligands, partially lacking the structural features, thus resulting in poor
enantioselectivity.
Keywords:
Diethylzinc
Ó 2014 Elsevier Ltd. All rights reserved.
Vasicine
Tridentate ligand
Enantioselective
The development of an efficient catalytic system for the enan-
tioselective carbonAcarbon bond formation is a major challenge
in organic synthesis. The enantioselective addition of diethylzinc
to aldehydes serves as a test reaction for the development of
tridentate ligand for enantioselective addition of diethylzinc to
aldehydes.
In order to investigate the catalytic properties of L-vasicine (1),
asymmetric addition of diethylzinc to 4-chlorobenzaldehyde was
selected as a model reaction. The use of 10 mol % of ligand 1 in hex-
ane gave the desired product in low yield and enantioselectivity,
possibly due to the poor solubility of the catalyst in hexane
(Table 1, entry 1). Therefore, it was imperative to examine the role
of different solvents on the yield and enantioselectivity of the reac-
tion. Among the different solvents screened, toluene provided
encouraging results with excellent yields (98%) and enantioselec-
tivity (98%) (Table 1). Both increase and decrease in temperature
from 25 °C resulted in a decrease of enantioselectivity (80%) and
yields (Table 1, entries 5–7). The effects of the rigidity and flexibil-
ity of the ligands on enantioselectivity play important roles in their
1
new catalysts.
Generally these reactions are catalyzed by using bidentate
ligands such as aminoalcohols, diols, aminothiols, diamine, and
2
,3
their derivatives.
The literature reports also indicate that a
bidentate chiral ligand (M1) in the presence of an achiral activator
ligand (M2) results in improved enantioselectivity and reaction
4
rate (Fig. 1). Besides, there are a few examples known in the liter-
ature, wherein tridentate ligands have been employed to effect the
5
addition.
While working with natural alkaloid vasicine (1),6 a close look
at its structure indicated that it possesses all the requisite features
of a tridentate ligand that is, having chiral ligand M1 as well as an
activator M2 within its chemical arrangement (Fig. 1). It was also
assumed that it may provide a more rigid arrangement of atoms
through N,N,O-complex, exhibiting better discrimination between
the two enantiotopic faces of an aldehyde within the transition
state complex. Keeping in view the above mentioned findings, it
was reasoned that the vasicine (1), can be employed as a chiral
7
catalytic activity. Therefore, to study the effect of rigidity of the 1,
N
M1
R
N
+
O
N
N
OH
M1
M2
M2
Chiral Ligand Chiral activator or
(1) Contain both M1
Achiral activator
and M2
q
Institute’s publication No. IIIM/1644/2014.
R= Alkyl,Aryl.
⇑
Corresponding author. Tel.: +91 (191) 2569000–010; fax: +91 (191) 2569333/
569017.
2
Figure 1. Chiral ligand and activator.
040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
0