180° unidirectional bond rotation in a biaryl lactone artificial molecular motor prototype

Article abstract of DOI:10.1021/ol062428u

(Diagram presented) A bifunctional biaryl lactone has been synthesized that should be capable of iterative unidirectional aryl-aryl bond rotation via: (1) a diastereoselective lactone ring opening, (S)-1 to (P,S)-2 or (M,S)-2; (2) a chemoselective lactoni

Full text of DOI:10.1021/ol062428u

ORGANIC
LETTERS
2006
Vol. 8, No. 25
5841-5844
180° Unidirectional Bond Rotation in a
Biaryl Lactone Artificial Molecular Motor
Prototype
Bart J. Dahl and Bruce P. Branchaud*
Department of Chemistry and Materials Science Institute, UniVersity of Oregon,
Eugene, Oregon 97403
bbranch@uoregon.edu
Received October 3, 2006
ABSTRACT
A bifunctional biaryl lactone has been synthesized that should be capable of iterative unidirectional aryl
−aryl bond rotation via: (1) a
diastereoselective lactone ring opening, (S)-1 to (P,S)-2 or (M,S)-2; (2) a chemoselective lactonization, (P,S)-2 or (M,S)-2 to (S)-3; and (3) a
chemoselective hydrolysis, (S)-3 to (S)-1. Preliminary results of a racemic sample have indicated unidirectional 180 rotation with very high
directional selectivity per individual artificial molecular motor molecule through the first two steps of this sequence.
°
Synthetic molecular machines1 imitate the mechanical move-
ments of biological molecular machines2 as well as everyday
large-scale machines and machine parts. The most basic
requirement of a totally synthetic rotary molecular motor is
an iterative directed bond rotation via a controllable energetic
input.3 There must be a net rotation in one direction vs the
other for the system to be useful as a molecular motor. To
date, three general synthetic designs have been determined
to achieve iterative 360° net directed bond rotation: (1)
photochemical cis/trans isomerizations and thermal helix
inversions, rotating once about strained double bonds in four
steps;4 (2) enantioselective reduction of a biaryl lactone and
chemoselective relactonization requiring a total of 10 syn-
thetic steps, rotating once about the aryl-aryl bond;5 and
(3) photochemical alkene isomerizations and multiple chemi-
cal transformations, rotating once about two fused ring
systems in catenanes.6 There has been one synthetic system
(4) (a) Koumura, N.; Zijistra, R. W. J.; Van Delden, R. A.; Harada, N.;
Feringa, B. L. Nature 1999, 401, 152-155. (b) Ter Wiel, M. K. J.; Van
Delden, R. A.; Meetsma, A.; Feringa, B. L. J. Am. Chem. Soc. 2003, 125,
15076-15086. (c) Vicario, J.; Meetsma, A.; Feringa, B. L. Chem. Commun.
2005, 5910-5912. (d) Vicario, J.; Walko, M.; Meetsma, A.; Feringa, B. L.
J. Am. Chem. Soc. 2006, 128, 5127-5135. (e) Geertsema, E. M.; Koumura,
N.; ter Wiel, M. K. J.; Meetsma, A.; Feringa, B. L. Chem. Commun. 2002,
2962-2963. (f) Koumura, N.; Geertsema, E. M.; Meetsma, A.; Feringa, B.
L. J. Am. Chem. Soc. 2000, 122, 12005-12006. (g) van Delden, R. A.; ter
Wiel, M. K. J.; de Jong, H.; Meetsma, A.; Feringa, B. L. Org. Biomol.
Chem. 2004, 2, 1531-1541. (h) Koumura, N.; Geertsema, E. M.; van
Gelder, M. B.; Meetsma, A.; Feringa, B. L. J. Am. Chem. Soc. 2002, 124,
5037-5051. (i) van Delden, R. A.; Koumura, N.; Schoevaars, A.; Meetsma,
A.; Feringa, B. L. Org. Biomol. Chem. 2003, 1, 33-35.
(1) (a) Balzani, V.; Credi, A.; Venturi, M. Molecular DeVices and
Machines; Wiley-VCH: Weinheim, Germany 2003. (b) Balzani, V.; Credi,
A.; Raymo, F. M.; Stoddart, J. F. Angew. Chem., Int. Ed. 2000, 39, 3348.
(2) Schliwa, M. Molecular Motors; Wiley-VCH: Weinheim, Germany,
2003.
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2005, 310, 80-82.
(3) Mandl, C. P.; Ko¨nig, B. Angew. Chem., Int. Ed. 2004, 43, 1622.
10.1021/ol062428u CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/08/2006

that has achieved 120° net directed bond rotation using purely
chemical transformations, rotating about a single bond in a
triptycene.7 We have reported an achiral biaryl lactone system
capable of 180° directed bond rotation in two steps about
an aryl-aryl bond using two different chiral nucleophilic
lactone cleavages and relactonizations.8
In this paper, we report an original design of a totally
synthetic rotary molecular motor based on a chiral biaryl
lactone structure. The design and synthesis of a similar
monofunctional system has been reported.9 However, direct
characterization of the rotation in that system was not
possible due to rapid equilibration of diastereomeric inter-
mediates, scrambling information about the direction of bond
rotation. Herein, we report the synthesis of the proposed
bifunctional motor and preliminary results of an experimen-
tally determined 180° directed bond rotation about the aryl-
aryl bond. Under the appropriate reaction conditions, this
system should be capable of a 360° unidirectional bond
rotation in six steps, which would be the most efficient purely
chemically driven motor system to date.
analysis of diastereomer ratios. The absolute direction of the
initial 90° rotation can be controlled completely through the
chirality of (S)-1 and the kinetics of the atroposelective
lactone ring opening. Through chemoselective carboxylic
acid activation, relactonization should occur to afford (S)-3.
This would result in another 1/4 turn about the aryl-aryl bond
from (M,S)-2 or (P,S)-2 to (S)-3 resulting in a 180°
unidirectional rotation relative to (S)-1. The directionality
of this step is completely dependent on the orthogonal
reactivity of the carboxyl moiety relative to the opposing
CdO(Nu) functionality in the lactonization process. There-
fore, regardless of the initial atropisomer formed in excess,
(M,S)-2 or (P,S)-2, unidirectional rotation at the relacton-
ization step is inherent. To achieve iterative directed bond
rotation, lactone (S)-1 must be reformed by selective cleavage
of the CdO(Nu) moiety on (S)-3 in the presence of the
lactone moiety.11
Racemic lactone 1 was synthesized in 11 steps in a 6.6%
overall yield (Scheme 2). Xylene 4 was oxidized and
Tri-ortho-substituted chiral biaryl lactone (S)-1 should
undergo diastereoselective ring cleavage via nucleophilic
attack at the lactone to afford either (M,S)-2 or (P,S)-2 in
excess, resulting in a 90° directed aryl-aryl bond rotation
(Scheme 1). Unless one of the ortho substituents is small,
Scheme 2. Racemic Synthesis of Proposed Motor 1
Scheme 1. Proposed Iterative Directed Aryl-Aryl Bond
Rotation
esterified to afford dimethyl ester 6. This was then reacted
tri-ortho-substituted biaryls are stable atropisomers that do
not interconvert,10 and thus the intermediates (M,S)-2 and
(P,S)-2 should be amenable to characterization by simple
under Leadbeater Suzuki coupling conditions12 with boronic
(7) (a) Kelly, T. R.; De Silva, H.; Silva, R. A. Nature 1999, 401, 150-
152. (b) Kelly, T. R.; Silva, R. A.; De Silva, H.; Jasmin, S.; Zhao, Y. J.
Am. Chem. Soc. 2000, 122, 6935-6949.
(8) Lin, Y.; Dahl, B. J.; Branchaud, B. P. Tetrahedron Lett. 2005, 46,
8359-8362.
(6) (a) Leigh, D. A.; Wong, J. K. Y.; Dehez, F.; Zerbetto, F. Nature
2003, 424, 174-179. (b) Hernandez, J. V.; Kay, E. R.; Leigh, D. A. Science
2004, 306, 1532-1537.
5842
Org. Lett., Vol. 8, No. 25, 2006

acid 7 resulting in biaryl 8. Grignard addition of 4-bromo-
1-butene to the aldehyde moiety was followed by a trieth-
ylsilane reduction of the resulting benzyl alcohol functionality
to afford 10. An oxidative alkene cleavage with catalytic
OsO4 and excess oxone13 afforded 11 which then underwent
an intramolecular Friedel-Crafts acylation sequence resulting
in tetralone 12. The ester functionalities were then hydro-
lyzed. The tetralone was reduced with NaBH4, and two
functionalities were lactonized in the presence of neat
trifluoroacetic acid to afford the proposed biaryl lactone
motor (S)-1/(R)-1 as a racemic mixture.
Attempts to reduce the sterically hindered tetralone moiety
on 12 to afford enantiomerically enriched samples of (S)-1
or (R)-1 using conventional chiral reducing agents were
unsuccessful. However, proof of concept of unidirectional
bond rotation is inherent as characterization of the racemic
mixture vs an enantiomerically pure sample would be
equivalent via NMR spectroscopy.14
Because of the poor solubility and difficulty purifying the
intermediates (M,S)-13/(P,R)-13 following ring cleavage of
(S)-1/(R)-1, a portion of the crude mixture was directly
derivatized to the more soluble allyl ester (M,S)-15/(P,R)-
15. NMR analysis of the purified products and side products
in the allyl ester formation indicated only one racemic
component, (M,S)-15/(P,R)-15, and thus very high rotational
selectivity for the lactone cleavage step.17
To confirm the relative axial stereochemistry of the ring-
opened intermediates (M,S)-13/(P,R)-13, a sample of (M,S)-
15/(P,R)-15 was studied by qualitative transient 1H NOESY-
1D. The irradiated amide hydrogen exhibited no NOE
interactions with the benzyl hydrogen ipso to the hydroxyl
on the lower ring but did have NOE interactions with the
hydroxyl hydrogen (Figure 1). To obtain a sample with the
Racemic motor (S)-1/(R)-1 was subjected to lactone
cleavage under Weinreb conditions15 in the presence of
cumylamine and AlMe3 to afford the ring-opened amide
(M,S)-13/(P,R)-13 with very high diastereoselectivity (Scheme
3). Following this, a portion of the crude mixture was
Scheme 3. 180° Directed Aryl-Aryl Bond Rotationa
Figure 1. Transient 1H NOESY-1D data for amide N-H protons.
opposite axial chirality, lactone (S)-14/(R)-14 was hydrolyzed
to afford (P,S)-13/(M,R)-13 and was directly converted to
allyl ester (P,S)-15/(M,R)-15 and studied by qualitative
transient 1H NOESY-1D. The irradiated amide hydrogen on
a Conditions used: (a) PhC(CH3)2NH2, AlMe3, CH2Cl2, reflux;
(b) DCC, DMAP, DMAP‚HCl, CHCl3, reflux.
(12) Leadbeater, N. E.; Marco, M. J. Org. Chem. 2003, 68, 888-892.
(13) Travis, B. R.; Narayan, R. S.; Borhan, B. J. Am. Chem. Soc. 2002,
124, 3824-3825.
(14) Racemic 1 can be used to study directed bond rotation by NMR
spectroscopy because each enantiomer of 1 can undergo a diastereoselective
directed bond rotation process (see Scheme 1), with each enantiomer rotating
in the opposite direction. Each step in the directed bond rotation for each
enantiomer will be observed as the same diastereoselective reaction by NMR
spectroscopy.
immediately lactonized under Keck conditions16 to afford
biaryl lactone (S)-14/(R)-14, thus achieving 180° aryl-aryl
bond rotation with very high rotational selectivity.
(15) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977,
4171-4174.
(9) Dahl, B. J.; Branchaud, B. P. Tetrahedron Lett. 2004, 45, 9599-
9602.
(16) Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50, 2394-5.
(17) One can assume on the basis of the detection limits of NMR
spectroscopy that the diastereoselectivity is 90-100%. The loss of the other
diastereomer in the derivatization process could be possible but very unlikely
on the basis of NMR analysis of crude 13, indicating a single diastereomer.
Given that the overall yield of the two-step ring opening and allyl
derivatization process was 72%, the rotational selectivity is at minimum
72% even if one diastereomer was not derivatized.
(10) (a) Eliel, E. L.; Wilen, S. H. In Stereochemistry of Organic
Compounds; John Wiley and Sons, Inc.: New York, 1994; pp 1142-1150.
(b) Bringmann, G.; Mortimer, A. J. P.; Keller, P. A.; Gresser, M. J.; Garner,
J.; Breuning, M. Angew. Chem., Ind. Ed. 2005, 44, 5384-5427.
(11) The motor should also rotate unidirectionally following the same
sequence of reactions (Scheme 1) starting with enantiomer (R)-1, in the
opposite direction about the aryl-aryl bond.
Org. Lett., Vol. 8, No. 25, 2006
5843

(P,S)-15/(M,R)-15 was determined to have NOE interac-
tions with the benzyl hydrogen ipso to the hydroxyl moiety
but had no NOE interactions with the alcohol hydrogen
(Figure 1).
To achieve iterative bond rotations, we made several
attempts to hydrolyze the cumylamide moiety of (S)-14/(R)-
14 chemoselectively. Both TFA and BF3 have been reported
to cleave the dimethylbenzyl group on secondary cumyl-
amides to afford primary amides.18 It has also been reported
that primary amides can be hydrolyzed in the presence of
esters with CuCl2 and glyoxal.19 However, when (S)-14/(R)-
14 was subjected to either TFA or BF3 using either stoi-
chiometric amounts or a large excess, no reaction occurred.
Thus, experimental conditions have not yet been discovered
to achieve an iterative directed bond rotation process in this
system.
In conclusion, preliminary results have shown that that
biaryl lactone (S)-1/(R)-1 is capable of unidirectional rotation
about the aryl-aryl bond. Lactone (S)-1/(R)-1 was deter-
mined to achieve 180° unidirectional rotation in two steps:
(1) (S)-1/(R)-1 f (M,S)-13/(P,R)-13 and (2) (M,S)-13/(P,R)-
13 f (S)-14/(R)-14 with very high directional selectivity.
The amide functionality in (S)-14/(R)-14 was unable to be
selectively hydrolyzed. Current investigations of other amide
nucleophiles that are designed to be selectively cleavable in
the presence of a lactone are underway. An alternate syn-
thesis of (S)-1 or (R)-1 to achieve an enantiomerically pure
sample is also in progress. This synthetic motor system
requires the sequential exposure to different conditions to
achieve rotation which, using the current conditions de-
scribed, would make it difficult to achieve continuous rota-
tion in one solution. Nevertheless, this system is now only
one of four known purely chemically driVen molecular motor
designs that has been experimentally determined to achieve
directed bond rotation.
Thus, we have determined that the first step in the
unidirectional aryl-aryl rotation in (S)-1 or (R)-1 results in
(M,S)-13 or (P,R)-13, respectively, with very high diaste-
reoselectivity. Because of this and the inherent directed bond
rotation in the relactonization step ((M,S)-13 or (P,R)-13 to
(S)-14 or (R)-14), (S)-1 and (R)-1 are both potentially
excellent chemically driven synthetic molecular motors.
The high atroposelectivity of the ring-opening reactions
is due to an axial preorganization (M/P) of the ortho-carboxyl
moiety in (S)-1/(R)-1 behind the plane of the tetrahy-
dronapthol ring and the lactone moiety protruding in front
of the ring, as determined by the X-ray crystal structure
(Figure 2). The cleavage of the lactone ring (S)-1 or (R)-1
Acknowledgment. We thank Dr. Lev Zakharov of the
University of Oregon CAMCOR facilities for his assistance
in determining the crystal structure of racemic 1. We are
grateful to NSF-IGERT DGE-0114419 for financial support.
Figure 2. Molecular structure of motor 1. The Chem 3D structure
of (S)-1 (in a racemic mixture) using coordinates obtained by X-ray
crystallography. The Chem 3D structure is shown to clearly illustrate
the lowest-energy conformation with M axial chirality.
Supporting Information Available: Experimental pro-
cedures and characterization data for all synthetic steps,
including 1H and 13C NMR spectra. 1H NOESY-1D spectra
for (M,S)-15/(P,R)-15 and (P,S)-15/(M,R)-15 are provided.
X-ray crystallographic data (cif file) for 1 is also provided.
This material is available free of charge via the Internet at
http://pubs.acs.org.
with M or P axial chirality results in an atropisomer that
preserves this axial stereochemistry (M,S)-13 or (P,R)-13,
respectively. Nucleophilic addition most likely occurs at the
unhindered exo face of the carbonyl. However, facial
selectivity in this system is inconsequential as the tetrahedral
intermediate can easily obtain a geometry to eliminate to
afford the atropisomer consistent with the preorganized M
or P axial configuration.
OL062428U
(18) Metallinos, C.; Nerdinger, S.; Snieckus, V. Org. Lett. 1999, 1, 1183-
1186.
(19) Singh, L.; Ram, R. N. J. Org. Chem. 1994, 59, 710-711.
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