Net directed 180° aryl-aryl bond rotation in a prototypical achiral biaryl lactone synthetic molecular motor

Article abstract of DOI:10.1016/j.tetlet.2005.09.151

Net directed 180° bond rotation was achieved through diastereoselective ring-opening reactions in an achiral biaryl lactone using a chiral nucleophile followed by re-lactonization. The efficiency of the directed bond rotation has been determined by HPLC-MS to be 50% and 20% with two different chiral nucleophiles. These results demonstrate the potential for a prototype of a chemically driven synthetic molecular motor which has the advantages of both simplicity and flexibility in operation and is the first example of the use of a chiral auxiliary to induce transient axial chirality resulting in net directed bond rotation.

Full text of DOI:10.1016/j.tetlet.2005.09.151

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8359–8362
Net directed 180° aryl–aryl bond rotation in a prototypical achiral
biaryl lactone synthetic molecular motor
Ying Lin, Bart J. Dahl and Bruce P. Branchaud*
Department of Chemistry, Materials Science Institute, Oregon Nanoscience and Microtechnologies Institute,
University of Oregon, Eugene, OR 97403-1253, USA
Received 23 September 2005;accepted 26 September 2005
Available online 14 October 2005
Abstract—Net directed 180° bond rotation was achieved through diastereoselective ring-opening reactions in an achiral biaryl lac-
tone using a chiral nucleophile followed by re-lactonization. The efficiency of the directed bond rotation has been determined by
HPLC–MS to be 50% and 20% with two different chiral nucleophiles. These results demonstrate the potential for a prototype of
a chemically driven synthetic molecular motor which has the advantages of both simplicity and flexibility in operation and is the
first example of the use of a chiral auxiliary to induce transient axial chirality resulting in net directed bond rotation.
Ó 2005 Elsevier Ltd. All rights reserved.
9
Synthetic molecular machines are designed to imitate
the mechanical movements of everyday large scale ma-
chines and machine parts. The design of these artificial
molecular machines challenges organic chemists to syn-
thesize molecules that conform to desired dynamic
behaviors and the characterization of these systems pro-
vides a more lucid understanding of molecular motion.
have also been reported. We have reported the design
and synthesis of a chiral biaryl lactone that should func-
tion as a prototypical chemically driven molecular mo-
1
9
g
tor capable of repeated net directed 360° rotation.
Practical uses for totally synthetic rotary molecular
motors are still being hypothesized, however, prelimin-
ary studies have indicated that they may find useful
applications in tuning the properties of liquid crystalline
2
10
Biological rotary molecular motors are a spectacular
environments.
3
group of biological molecular machines that convert
energy (from chemical and electrochemical sources) into
a directed mechanical rotation, producing useful work.
The most basic requirement of a totally synthetic rotary
molecular motor analog is an iterative directed bond
In this letter, we report a new approach to the design of
totally synthetic rotary molecular motors, using an achi-
ral motor with chiral reagents to drive the unidirectional
rotation. Bringmann et al. have found that ring open-
4
11
rotation via a controllable energetic input. There must
ings of biaryl lactones with both chiral amides and chi-
1
2
be a net rotation in one direction versus the other in
order for the system to be useful as an artificial molecular
ral alkoxides lead to high diastereoselectivity in the
formation of atropisomeric biaryls. Using chiral nucleo-
philes in diastereoselective ring openings to produce
atropisomeric biaryls is also well established in the syn-
thesis of natural products containing atropisomeric bi-
5
motor. To date there have been only two general syn-
thetic systems that have been experimentally determined
to achieve iterative 360° biased net directed bond rota-
6
,7
13
tion and one synthetic system that has been experi-
aryl stereochemistry. Herein, we report how this
mentally determined to achieved 120° biased net
concept can be extended to the design of synthetic
molecular motors.
8
directed bond rotation. Several theoretical designs, syn-
theses, and studies of experimentally unverified pro-
posed net unidirectionally rotating molecular systems
Achiral lactone 1 (Scheme 1) should exist as a rapidly
interconverting pair of enantiomers by a slight back
1
4
and forth pivoting about the biaryl bond. Diastereo-
selective (atropisoselective) ring opening of 1 with an
appropriate chiral nucleophile, acting as a chiral auxil-
iary, should generate predominantly one axial diastereo-
mer, shown as 2a in Scheme 1, resulting in a net 90°
Keywords: Molecular motors;Molecular machines;Directed bond
rotation.
*
Corresponding author. Tel.: +1 541 346 4627;fax: +1 541 346
645;e-mail: bbranch@oregon.uoregon.edu
4
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.151

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Y. Lin et al. / Tetrahedron Letters 46 (2005) 8359–8362
Scheme 2. Reactions of lactone 1 to demonstrate directed bond
rotation using an amine nucleophile (see text for detailed discussion).
compared to 6a/6b due to the adoption of a near-planar
geometry, allowing for stabilizing delocalization across
the two aryl rings of the biaryl system. Similar behavior
of comparable biaryl lactones has been reported. The
ring opened form is favored only under basic conditions
in which the carboxylic acid in its anionic form.
Scheme 1. General strategy to use repeated, iterative atropisoselective
lactone ring opening reactions to achieved directed bond rotation in
1
7
180° increments.
directed rotation. Cyclization of 2a with an appropriate
reagent should generate lactone 3, resulting in a net 180°
directed rotation. Cleavage of the chiral auxiliary (Nu*)
Attempts to isolate samples of 6a and 6b with milder
acid additions (2 N HCl acidified to pH 2.0 and 4.0 or
oxalic acid to pH 2.0 and 4.0) resulted in the desired
0
from 3 should generate 1 , in which the carbonyl would
1
18
be switched relative to its position in 1. Another cycle of
products being transiently observed by H NMR.
0
the same reactions would lead to 2a (270° rotation),
However, chromatographic purification necessary for
analysis of diastereomer formation consistently resulted
in complete conversion to cyclized lactone 7.
0
then 3 (360° rotation), then back to 1. The entire pro-
cess could then be repeated to result in iterative net uni-
directional bond rotation. The overall energy for the
bond rotation would come from the use of thermody-
namically favorable reactions at each step to drive the
directed bond rotation cycle forward.
In order to quantify the diastereoselectivity of the ring
opening, and hence determine the efficiency of the 180°
directed rotation, it was necessary to determine the ratio
of the stable anionic products of ring opening (5a and
5b) prior to treatment with acid. Lactone ring cleavage
of 1 with lithio(S)-1-phenylethanamine was performed
as described above. However, the solution was not acidi-
fied and the resulting crude mixture of 5a and 5b was
isolated via evaporation. Analysis of the mixture was
achieved by reverse-phase HPLC–MS, reproducibly
resulting in a clean separation and identification of the
The synthesis of lactone 1 was performed in two steps
following the modified literature procedures from com-
mercially available diphenic acid 4 by Haworth cycliza-
tion followed by Baeyer–Villiger oxidation.16 Lactone
ring opening of 1 with lithio(S)-1-phenylethanamine in
THF at room temperature resulted in the formation of
amide axial diastereomers 5a and 5b (Scheme 2). Subse-
quent acidification of the mixture with 2 N HCl led
directly to the isolation of lactone 7 in a 58% yield with
expected products 6a and 6b being undetected. The bia-
ryl lactone 7 should be thermodynamically favorable
15
1
8
two major peaks (5a and 5b) in a ratio of 3:1. Net
180° directed rotation is inherent in the diastereoselec-
tive ring opening and subsequent lactonization. Due to
the instability of the intermediate products, the absolute

Y. Lin et al. / Tetrahedron Letters 46 (2005) 8359–8362
8361
stereochemistry of the major and the minor axial diaste-
reomers could not be elucidated.
bond rotation. Simple one-pot switching of basic (nucleo-
philic) and acidic conditions would drive the continuous
rotation of 1. Flexibility in the choice of fuel usage is
also a key advantage, in that any chiral nucleophile
could potentially drive net unidirectional rotation in this
system. These two factors are especially relevant when
considering the more sophisticated chemically driven
synthetic motor systems reported to date: one of which
1
9
In a similar system, net unidirectional 180° aryl–aryl
bond rotation of lactone 1 was again achieved using a
menthol nucleophile, lithio(1R,2S,5R)-2-isopropyl-5-
methylcyclohexanol (Scheme 3). Subsequent acidificat-
ion did not lead to isolable samples of 11a and 11b
but instead led directly to lactone 12 in a 34% yield.
After direct evaporation of the crude product, HPLC–
MS analysis of anions 10a and 10b reproducibly led to
a clean separation of the diastereomers in a ratio of
6
b
is reversible and more efficient in rotation but makes
use of very specific and time-consuming multistep reac-
6
tion sequences and the other being unable to surpass a
7
120° directed rotation.
1
8
3
:2. Net 180° directed rotation is inherent in the diaste-
reoselective ring opening and subsequent lactonization.
Due to the instability of the intermediate products, the
absolute stereochemistry of the major and the minor
Current efforts are focused on discovering reaction con-
ditions to selectively hydrolyze amide 7 and ester 12 in
the presence of the lactone group. The relative reactivi-
ties of the aforementioned functionalities to conven-
tional acid or base hydrolysis makes this a difficult
task and previous attempts have been unsuccessful. An
alternate approach is also currently being pursued using
different chiral nucleophiles which generate intermedi-
ates from which the chiral auxiliary is more easily
cleaved or that can be cleaved under orthogonal (e.g.,
redox or light) conditions. Realization of these studies
would result in 360° iterative directed rotation in a
new biaryl molecular motor system with the advantages
of greatly simplified operation and flexibility in fuel
usage.
1
9
axial diastereomers could not be elucidated.
These two examples demonstrate directed bond rotation
in a new prototypical biaryl molecular motor system. In
the case of the amide system, the directed 180° bond
rotation of 1 to 7 is 50% efficient and in the ester system
the directed 180° bond rotation of 1 to 12 is 20% effi-
cient. Although the rotational efficiency may be a draw-
2
0
back, the overall simplicity of this biaryl system should
be advantageous. In principle, systems analogous to
prototypical molecular motor 1 could be used for pro-
cessive (iterative, repeated) cycles of net unidirectional
In summary, these results are the first examples of pro-
totypical molecular motors driven by chiral auxiliaries.
In each case, the chiral auxiliary induces transient axial
chirality, resulting in net directed bond rotation.
Acknowledgements
We are grateful to NSF-CHE-9986926, PRF #35372AC-
1,
the US Department of Education GAANN
P200A010222-03, and the NSF-IGERT DGE-0114419,
for financial support.
Supplementary data
Experimental procedures and characterization of all
compounds as well as HPLC–MS procedures and data.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.tetlet.2005.09.151.
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