Conformative coupling of two conformational molecular switches

Article abstract of DOI:10.1002/anie.200352130

Passing on information. Two conformational switches, decalin units, were coupled to a 14-membered bislactam ring (see formula, TBDPS=tert-butyldiphenylsilyl). Removal of a bisacetal clamp on the left side of the molecule resulted in a double ring-flip of

Full text of DOI:10.1002/anie.200352130

Communications
Biconformational Bisdecalin Switch
Conformative Coupling of Two Conformational
Molecular Switches**
Michael Karle, Dirk Bockelmann, Dirk Schumann,
Christian Griesinger,* and Ulrich Koert*
A molecular switch consists of a molecule that can reversibly
change states (on, off) upon an external stimulus.[1] There are
photoswitches/chiroptical switches,[2] redox switches,[3] switch-
able rotaxanes and catenanes,[4] and switchable allosteric
receptors.[5] Conformational switches have a biconforma-
tional basic framework. Biconformational cis-decalins[6] and
cis,anti,cis-perhydroanthracenes[7] are suitable conforma-
tional switches for the transduction of molecular signals
through conformational transmission.[8]
A 2,3,6,7-tetrasubstituted cis-decalin of type 1 has the two
low-energy conformations 2 and 3 (Scheme 1).[6] A Newman
ꢀ
projection along the three green C C bonds in 1 illustrates
the hinge function of these three bonds in the double ring-flip
4!5.
In order to span greater distances with conformational
switches (e.g. for signal transduction) or to use conforma-
tional switches in molecular circuits, one has to solve the
problem of coupling two or more of these switches together.[9]
Here we investigate whether a 14-membered macrobislactam
of type 6 can be used for the conformational coupling of two
cis-decalin switches.[10] Molecular modeling studies indicated
that two low-energy conformations of the 14-membered ring
should exist: one with an all-equatorial arrangement of the
four junctions to the decalins (positions 2, 3, 6’, and 7’ in 6)
and one with an all-axial arrangement. Here we report on the
synthesis of 6 and on studies with regard to the conformative
coupling of the two decalins. We wondered whether a double
ring-flip in the “left” decalin can induce, through the 14-
membered bislactam ring, a double ring-flip of the “right”
decalin.
Scheme 1. The tetrasubstituted cis-decalin 1, its double ring-flip 2!3
(as a Newman projection 4!5), and the prototype of a coupled bis-
decalin, 6.
lective synthesis of the tetrasubstituted cis-decalins was
required (Scheme 2). To this end we modified our previous
synthesis by using a diastereoselective Diels–Alder reac-
tion[11] of dimenthyl fumarate (7) with 1,3-butadiene to obtain
The known synthesis of tetrasubstituted decalins of type 1
led to the racemic product only.[6a] However, to connect two
decalins in a predictable and controlled way an enantiose-
[*] Prof. Dr. U. Koert, Dipl.-Chem. M. Karle, Dipl.-Chem. D. Schumann
Fachbereich Chemie
Philipps-Universität Marburg
Hans-Meerwein-Strasse, 35032 Marburg (Germany)
Fax: (+49)6421-2825-677
E-mail: koert@chemie.uni-marburg.de
Prof. Dr. C. Griesinger, Dipl.-Chem. D. Bockelmann
Max-Plank-Institut für Biophysikalische Chemie
NMR-Based Structural Biology
Am Fassberg 11, 37077 Göttingen (Germany)
Fax: (+49)551-201-2201
E-mail: cigr@mpibpc.mpg.de
[**] This work was supported by the Volkswagen Foundation, the
Deutsche Forschungsgemeinschaft, the Max-Planck-Gesellschaft,
the Fonds der Chemischen Industrie, and the Pinguin Foundation.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 2. Enantioselective synthesis of the tetrasubstituted azido-
aminomethyldecalin 11. TBDPS=tert-butyldiphenylsilyl.
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DOI: 10.1002/anie.200352130
Angew. Chem. Int. Ed. 2003, 42, 4546 –4549

Angewandte
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the cyclohexene 8, which was transformed into alcohol 9 in a
few steps. The two primary OH groups were differentiated by
formation of the benzylidene acetal 10, which could be
converted into the azidoaminomethyldecalin 11 (see Sup-
porting Information). Compound 11 represents the com-
pletely functionalized left decalin unit of 6.
A key step in the synthesis of the right decalin unit was the
regioselective opening of the enantiomerically pure epoxide
12 with benzyl alcohol to give the trans-diaxial b-benzyloxy
alcohol 13, which was converted via the allyl ether 14 into the
carboxylic acid 15 (Scheme 3 and Supporting Information).
Scheme 4. Connection of both decalin units to the amide 16 and ring
closure to the bislactam 17. DIPEA=diisopropylethylamine, HATU=2-
(1-hydroxy-7-azabenzotriazol-1-yl)-1,1,3,3,-tetramethyluronium hexa-
fluorophosphate, HBTU=2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethy-
luronium hexafluorophosphate, HOAt=1-hydroxy-7-azabenzotriazole,
HOBt=1-hydroxybenzotriazole.
Scheme 3. Synthesis of the enantiomerically pure decalin 15.
The formation of the 14-membered bislactam 17 started
with the HBTU-mediated coupling of 11 and 15 to the amide
16 (Scheme 4). Hydrolysis of the ethyl ester and reduction of
the azide provided an aminocarboxylic acid, which was
cyclized to provide the target bislactam 17.
resulting structural information (see Supporting Information)
was again used in molecular modeling calculations, which led
to several low-energy conformations. In these unequivocal,
related structures (e.g. 21 in Scheme 5) the decalins assume a
double-chair structure and the 14-membered bislactam ring
has local variations. In the left decalin unit the substituents at
C6 and C7 are now in axial positions.[13] This results in a
double ring-flip of the left decalin, which leads to equatorial
positions for the substituents at C2and C3. This conforma-
tional change is transduced by the 14-membered ring to the
right decalin unit, resulting in a double ring-flip. The
substituents at C6’ and C7’ assume equatorial positions, and
the substituents at C2’ and C3’ switch from equatorial to axial
positions.
This is the first example of the conformative coupling of
two decalin switches through a 14-membered bislactam ring.
The switching distance from the left- (C6, C7) to the right-
hand side (C2’, C3’) of the molecule is approximately 15 Š. It
may be possible to couple more than two biconformational
decalins in series. A functional chain of three decalin switches
coupled by two 14-membered bislactam rings should be long
enough to bridge the lipophilic part of a phospholipid bilayer
and to transfer signals across membranes.
The bisacetal group in 17 fixes the O substituents at C6
and C7 in equatorial positions. The overall structure of 17,
which is determined by this covalent clamp on the left decalin
unit, and in specifically the pattern of axial/equatorial
arrangements of the four substituents of each decalin unit,
was determined unequivocally by DQF-COSY and ROESY
experiments in CDCl3. The resulting structural parameters
(for ROE contacts and torsion angles, see the Supporting
Information) were used as input for molecular modeling
(InsightII/Discover, CVFF). Ten low-energy structures (e.g.
18 in (Scheme 5) were calculated in which the two decalins
have the same double-chair conformation but the 14-mem-
bered bislactam has local differences .
The bisacetal group of the left decalin unit forces the
substituents at C6 and C7 into equatorial positions, which
fixes the substituents at C2and C3 in axial positions. This in
turn leads to an axial orientation of the C6’ and C7’
substituents on the right decalin unit, which brings the C2’
and C3’ substituents at the right end of the molecule into
equatorial positions.
The covalent bisacetal clamp[12] of the left decalin unit was
cleaved by reaction with HF, which remarkably did not affect
the TBDPS groups. The resulting diol was protected as the
diacetate 20 in order to facilitate the NMR analysis. The
In conclusion, we have described the conformative
coupling of two biconformational decalins though a 14-
membered bislactam ring. This paves the way for the use of
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Scheme 5. The cleavage of the bisacetal clamp (17!20) leads to a double ring-flip in the left decalin unit, which induces a double ring-flip of the
right decalin by conformative coupling of the 14-membered bislactam ring (18!21, 19!22). Structures 19 and 22 are Newman projections along
ꢀ
the C C bonds in green in 17 and 20, respectively.
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Keywords: conformational analysis · decalin ·
molecular devices · NMR spectroscopy · synthesis
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