Tetrahedron Letters
Highly stereoselective anti-aldol reactions catalyzed by simple
chiral diamines and their unique application in configuration
switch of aldol products
a
Lei Li a, Shaohua Gou a,b, , Fei Liu
⇑
a Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China
b Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research, Southeast University, Nanjing 211189, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 July 2013
Revised 31 August 2013
Accepted 13 September 2013
Available online 20 September 2013
Chiral derivatives of trans-1,2-diaminocyclohexane with different N,N-dialkyl groups in well-defined ori-
entations have been synthesized, and applied as catalysts for the asymmetric aldol reaction between a
variety of aldehydes and ketones. Enantiomeric catalyst 1j catalyzed the reaction in ethanol and provided
excellent diastereoselectivity and enantioselectivity. Significantly, simple replacement of organic sol-
vents with water switched the products of the aldol reactions from anti to syn configuration. Such cata-
lytic reactions led to the products with anti to syn diastereoselectivity up to 99:1 in ethanol, while in
water gave the products with syn to anti diastereoselectivity up to 99:1.
Keywords:
Aldol reaction
Organocatalysts
Chiral diamines
Configuration transformation
Enantioselectivity
Ó 2013 Elsevier Ltd. All rights reserved.
The aldol reaction is one of the most fundamental tools for the
construction of carbon–carbon bonds, it can produce b-hydroxyl
carbonyl compounds, which are key intermediates or synthetic
building blocks for many natural products and drugs.1
diaminocyclohexane (abbreviated as DACH) derivatives, which are
stable and easy to obtain and modify, has received rapidly growing
attention. However, most successful DACH based catalysts are
involved with the modification of the monoamines, for example
lactamization, sulfonamidization, and thioureation,6 mimicking
enzymatic activities.1h,6a,6b,7
Chiral N,N-dialkyl diamines have been successfully applied by
Cheng2b,8 to catalyze a series of asymmetric aldol reactions. In their
reactions of cyclohexanone with aldehydes,8c the results with main
products in anti-configuration were fairly good (up to 95% yield,
10:1 anti/syn, 98% ee). However, no compounds in syn configura-
tion as major products were mentioned. To our knowledge, only
Gao and his co-workers9 recently reported a configuration switch
in asymmetric aldol reactions. In their experiments, a chiral dia-
mine combined with succinic acid could catalyze the syn-aldol
reaction of both cyclohexanone and cycloheptanone with five aro-
matic aldehydes (up to 94% yield, 1.8:1–5:1 syn/anti, 53–88% ee),
either by increasing the size of the additive acids or by introducing
a hydrogen-bond donor into the additive acids.
Asymmetric aldol reactions of ketones with aldehydes usually
offer chiral compounds with one or multiple stereocenters, and
such highly enantio- and diastereo-selective reactions generating
two stereocenters in one step are valuable for asymmetric synthe-
sis. Generally, four products with different mirror images derived
from the reaction of symmetric ketone and aromatic aldehyde
can be obtained as shown in Scheme 1. According to the previous
reports, chiral catalysts would generate the relevant products for
each pair of ketones and aldehydes, either syn2 or anti enantio-
mers.3 So far, in the reaction between cyclohexanone and
aldehydes, almost all of the organocatalyts are known to provide
anti-aldol adducts predominantly, albeit with a few limited excep-
tions which afford syn-products. Thus, employing one single chiral
catalyst to control the relative stereochemical configuration of
aldol products in such reactions is still challenging.
Since List and Barbas reported the direct aldol reaction of
Herein reported is a series of modified diamine catalysts
derived from DACH that exhibit excellent diastereoselectivity and
enantioselectivity in aldol reactions in ethanol, and their applica-
tion in the challenging syn-aldol reaction.
acetone with aryl aldehydes catalyzed by L
-proline4, many kinds
of proline-derivated catalysts have been developed for asymmetric
aldol reactions.3a,3b,3d,5 Recently, the application of chiral trans-1,2-
Modified diamine catalysts were synthesized starting from the
commercial chiral diamine 2. All catalysts except 1a and 1k were
easily prepared from 2 in a 4-step sequence as shown in Scheme 2,
whereas 1a was obtained by omitting step (c) and 1k was prepared
⇑
Corresponding author.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.