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Flexible Molecules with Defined ShapeЧConformational Design.

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Flexible Molecules with Defined Shape-Conformational
Design
By Reinhard W. Hoffmann"
Chemists have for a long time considered molecules simply in terms of their constitution.
The importance of molecular shape was recognized perhaps for the first time by the semiochemists, who were interested in the interactions of fragrant substances with a receptor. Apart
from the case of rigid molecules, our ideas and concepts of molecular shape simply reflect an
instantaneous situation, because flexible molecules take advantage of the whole range of
conformation that is available to them. Nature frequently utilizes flexible molecules whose
conformational space is restricted, in other words, molecules that can adopt only a few
preferred conformations. This review discusses some of the principles that nature employs in
order to impart a defined shape to flexible molecules. The purposeful application of these
principles then allows the conformational design of molecular skeletons.
1. Introduction
The biological activity of many natural and synthetic substances is based on the fact that they bind to a receptor by the
interaction of specific functional groups. The receptors have
binding sites situated either in a pocket, in a cleft, or on the
surface. For optimal binding the functional groups of the
active substances complementary to those in the binding site
must have or adopt a specific spatial arrangement. In only a
few areas of biochemistry does nature use active substances
that are predominantly rigid, such as steroids. Often conformationally flexible substances are involved, which nonetheless adopt a specific preferred conformation,['] in other
words, they take on a defined shape. If the preferred conformation of the active substance is also that required by the
receptor, then the free energy of binding becomes more favorable in terms of both entropy and enthalpy. On the other
hand, the conformational mobility allows the particular substances to diffuse rapidly into and out of the receptor."]
The principles according to which nature imparts a defined shape to such molecules while largely preserving their
conformational mobility are of interest. In the case of
proteins and oligopeptides these principles are generally
known: the amide bond in these substances exists in the
preferred conformation 1 and has, thanks to the partial double-bond character, a rotation barrier of approximately
20 kcal mol - '.I2]
other things on the nature of the side-chain groups R. It is
known, for example, which amino acid sequences result as a
rule in the formation of an a helix or a p turn or, again, which
are typical of ,&sheet structures.[31In the area of the polypeptides one has therefore a general understanding of how structural elements affect the secondary structure, an understanding that can be utilized in designing peptide-like active
substances.[41
In the case of a biologically active substance that binds to
the receptor by a short peptide sequence, it should be irrelevant whether the remainder of the molecular skeleton is a
continuation of the peptide chain['] or has another struct ~ r e , ' ~as. ~long
]
as this produces a specific shape of the
overall molecule. Substances such as jaspamide (2)['] or
geodiamolide A (3)r81illustrate this clearly.
0
2
Although rotation about the amide bond is certainly still
possible, at any given moment the preferred conformation is
adopted almost exclusively. Preferred conformations exist
also along the other N-C, (dihedral angle 4) and C,-C=O
(dihedral angle $) skeletal bonds. Which preferred conformation is adopted in any particular case depends among
[*] Prof. Dr. R.W. Hoffmann
Fachbereich Chemie der Universitlt
Hans Meerwein Strasse, D-W-3550 Marburg (FRG)
1124 0 VCH
Verlugsgesellschuft mbH, W-6940 Weinheim, 1992
3
It may be concluded that the (propionogenic) partial
structures in 2 and 3 derived from the fatty acid metabolism
adopt quite specific preferred conformations as a consequence of the existing stereocenters, despite their obviously
unrestricted conformational mobility. Chemists dealing with
polyketide natural products are of course fully aware of
this.[g1The principles illustrated in nature could thus be utilized, and indeed should also be developed further, in order
to impart a specific shape to arbitrary molecular skeletons
while retaining conformational mobility. These principles
are a) the avoidance of g'g- interactions["] and b) the
avoidance of allylic 1,3 strain.
0570-0833/92/0909-l124 3 3.50+ .2Sj0
Angew. Chem. Int. Ed. Engl. 1992, 3f, 1124-1134
2. g+g- Interactions as a
Conformation-DeterminingFactor
The g'g- interaction (also termed syn-pentane interaction) brings two methyl (alkyl) groups, for example the
methyl groups of n-pentane (see 4 in Scheme 1) into such
spatial proximity as to produce a destabilizing steric interaction. The nature of the interaction is well known in the form
H3CxYC
k R' k
H
" t t " 5a
5
H3C
6
"g-g-" 5b
"k H k'
'tg" 6 a
"gt"6b
Scheme 2. Sa, b and 6a, bare the only conformations of 5 and 6 without ,qt,qinteractions.
Scheme 1. Left: Conformation of n-pentane (4) leading to g'g- interactions.
The cyclohexane ring drawn in dashed lines points out the analogy to 1,3-diaxial interactions. The g + and g- interactions are defined with the help of
sawhorse (middle) and Newman projections (right).
of the 1,3-diaxial interaction in cyclohexane derivatives. The
term g'g- interaction derives from the fact that the conformation of a molecule can be given as a sequence of the
dihedral angles of the principal chain. With a dihedral angle
of about 60" one has a gauche arrangement; with a dihedral
angle of + 60" one speaks of g', with one of - 60", of g - . A
dihedral angle of 180" corresponds to a trans arrangement ( 1 )
of the chain. The sign of the dihedral angle is independent of
whether the chain is analyzed from C1 to C4, or vice versa.
The arrangement in structure 4 is characterized, when one
looks at the principal chain of the molecule, by a g+ dihedral
angle followed by a g - dihedral angle.
Calculations[' '1 and experimentsr"] show that a 1,3-diaxial
interaction of two substitutents on a cyclohexane ring produces a destabilization of approximately 2.6-6.2 kcalmol- '.
This would also apply to the syn-pentane conformation 4
compared to the all-trans chain,['3314] if the molecule did not
decrease this strain by opening the dihedral angle to 8095".[14- '1 Nevertheless, the relaxed g'g- interaction still
produces a destabilization on the order of 1.4-3.0 kcal
mol-l.[lo,15. 181 The consequence of this is evident in the
partial structures 5 and 6,which in each case can adopt only
two conformations that are free of g'g- interactions[9b1
(Scheme 2, see also ref.['g, 'I).
The structural elements 5 and 6 are typical of propionogenic natural substances. An evaluation of the X-ray structure analyses of 30 arbitrarily chosen compounds containing
the partial structure 5 or 6 showed that in 46 out of 51 of
these structural elements the specific conformation adopted
is one in which the g+g- interaction is avoided. This is
demonstrated very clearly in the structure of a derivative of
bougeanic acid 7["] and in the partial structures of ionomycin (8)t221(Fig. 1).
Compounds with the unit 5 thus have a straight main
chain (tt conformation 5a, eight of thirteen cases, dihedral
angles 170 9") or more rarely (five of thirteen cases, dihedral angles 68 f11") a doubly bent chain (g+g+ or g - g conformation). The unit 6 necessarily leads to a simple bending of the main chain (tg conformation, 33 cases, dihedral
angles 171 6"; 62 _+ 8'). The structural formulas of a number of pheromones suggest that these molecules may have a
specific folding pattern despite complete conformational
mobility. For example, the shape of lardolure (9)[231
may
well be essential for its biological signaling action. Epimers
of 9[241having other preferred conformations of the chain
are ineffective.
9
The different preferred conformations of the partial structures 5 and 6 have been known already for a long time from
polymer chemistry. 5 corresponds to the repeating unit in
syndiotactic polypropylene, which exists either as an alltrans chain[25]or as a ttg'g' helix
6 corresponds to
isotactic polypropylene, in which the direction of the chain
changes at every other double bond in order to avoid g'ginteractions. The resulting tg' tg'tg' conformation likewise
leads to a helical structure 11[271(Scheme 3).
The stereotriads A-D frequently occur as structural elements in propionogenic natural substances.[281Whitesell and
Hildebrandt[291pointed out that these partial structures
have quite specific preferred conformations. An inspection
Reinhard W Hoffmann was born in Wiirzburg, Germany in 1933. He studied chemistry at the
University of Bonn and gained his doctorate in 1958 for research conducted with B. Helferich.
After two years as a postdoctorate with C. W Brindley at the Pennsylvania State University, he
became an assistent to G. Wittig at the University of Heidelberg, where he habilitated in 1964.
Three years later he was appointed as Dozent at the Technische Hochschule in Darmstadt. He has
been professor at the University in Marburg since 1970. At various times he has been a guest
professor at the University of Wisconsin, the University of Bern, and the University of California
at Berkeley. He is currently interested in developing methods for stereoselective C-C bond
formation and exploring their applications in natural products synthesis, as well as generally
studying the stereochemistry of reactive organometallic compounds.
Anxew. Chrm. Int. Ed. Engl. 1992, 31, 1124-1134
1125
r
ci
Scheme 3. a) Helical conformation of syndiotactic polypropylene 10 and b) of
isotactic polypropylene 11. T = trans, G = gauche.
COOH
OH
OH
0
0
8
If several hydroxyl groups on the main chain are at the
relative positions 1 and 3, the conformation of the main chain
can be stabilized additionally by hydrogen bonds if the hy-
?
A
Fig. 1. a) Chemical formula of bougeanic acid 7 and the crystal structure of a
derivative (R = CH,C(O)C,H,Br). b) Chemical formula of ionomycin (8) and
the crystal structure of its Ca 2+salt. In this and thefollowingfigures, the partial
structures relevant to the discussion are highlighted in black. The remaining
parts of the structures are reproduced in gray.
of the crystal structures of a random selection of 26 compounds with these structural elements show that the conformation of the main chain is again mainly determined by the
methyl branchings, as in the case of 5 and 6.In this respect
only the structural types 12 and 13 are significant with regards to conformation. The hydroxyl groups are oriented
outward into the free space independent of their relative
configuration, even in the case of folded chains, and may
interact either intramolecularly or intermolecularly.
1126
c
D
droxyl groups have an appropriate spatial arrangement;13'1
see for example the partial structures of rifamycin (14)L3I1or
zincophorin (15)r321
(Fig. 2 ) .
In the area of propionogenic natural substances, compounds are also found in which the conformational mobility
of the main chain is restricted, but not suppressed, by a fused
six-membered ring, as for example in the partial structures
16 and 17.
Fir1 and Kresse et a1.[331showed by NMR investigations
on terpenes that for these partial structures the illustrated
conformations are largely populated, in other words, exactly
those conformations in which a g+g- interaction is avoided.
Thus, the equatorial (in 16) or axial (in 17) position of the
substituent R determines the preferred conformation along
the C2-C7 bond. This was subsequently discussed in detail
also by Kishi et al.1341and Sih et al.1351Similar effects were
also observed in five-membered ring lac tone^.[^^] Finally, 14
randomly chosen X-ray structure analyses of propionogenic
natural substances show that corresponding partial strucAngew. Chem. tnt. Ed. Engl. 1992,31, 1124-1134
tion about the exocyclic bonds are fully possible at ambient
temperature.
Allinger et aI.I3'] referred early on to the fact that a
branched side chain in an axial position on a six-membered
ring, as in 18, adopts only a single preferred conformation in
order to avoid g'gThis arrangementr3'] is
~~]
found for example in the structure of z i n c o p h ~ r i n , ~(see
Fig. 2 bottom). However, even an unbranched axial side
chain can be fixed in space if an equatorial group is present
in the adjacent position, as in 19.rgb1Essentially, this is a
14
16
ia
17
R
H #H
Y
A
special case of the gem-dimethyl e f f e ~ t . [ ~ ' Likewise,
-~~]
a
defined orientation of an unbranched, equatorially situated
side chain can be achieved if it is located adjacent to a disubstituted ring position, as in 20. This relates to structural
elements that occur, for example in pederin (21))""' ont ~ a m i d e )m
~ ~y ]~ a l a m i d e , [and
~ ~ l bry~statin.[~']
A section of
OH
15
21
the crystal structure of 18-epi-ben~oylpedamide~~"~
illustrates this effect clearly (Fig. 3).
OCH3
Fig. 2. Because of the appropriate spatial arrangement of OH groups, the
conformations of rifamycin S (14, top) and zincophorin (15, bottom) are additionally stabilized by hydrogen bonds.
tures exist in exactly these conformations. One should keep
in mind that, notwithstanding the preference for these 'Onformations, both inversion of six-membered rings and rotaAngew. Chem. I n [ . Ed. Engl. 19!?2,31,1124-1134
18-epr- benzoylpedamlde
I
Fig. 3. Chemical formula and crystal structure of 18-epi-benzoylpedamide.
The orientation ofthe side chain is dictated by the two neighboring gem methyl
groups.
1127
In the structures examined hitherto the central atom of the
partial structures 5 and 6 was sp3-hybridized. If it is sp2-hybridized as in 22, the central bond angle is larger, so that the
methyl groups are better able to avoid one another. An analysis of a small number of randomly selected structures of
compounds of type 22 show a broad multiplicity of possible
conformations. The number of conformations that can be
adopted at room temperature is thus not noticeably restricted by g'g- interactions in this type of structure.
change in the direction of the main chain is not identical to
that which occurs in compounds with the partial structure 6
as discussed in Section 2.
The conformation-determining action of the allylic 1,3
strain is illustrated, for example, in the compounds stegobinone (26) and 1'-epi-stegobinone (27),[531
of which the for-
26
22
27
23
If the central atom of the structural units 5 and 6 is an
oxygen atom, however, as in 23, then the shorter C-0-C distances and the smaller c - 0 - C bond angles mean that giginteractions become more pronounced. This is reflected, for
example, in the preferred conformation of diisopropyl ether
23.[491
mer is the sex pheromone of the drugstore beetle, stegobium
paniceum, whereas the 1' epimer inhibits the pheromone action (Fig. 4).[541
0
0
3. Allylic 1,3 Strain as a
Conformation-DeterminingFactor
Allylic 1,3 strain was defined by Johnson,[5o1who stated
that in partial structures of the type 24 (RZ H) those conformations in which the groups R and RZare coplanar, as in
24 a, are energetically unfavorable. The preferred conformation is 24b, in which the H-C-C=C-RZ unit lies in one plane.
+
248
24b
25
Recent calculations show["' that conformation 24b is almost exclusively populated, and that conformation 24 a is
approximately 3.5 kcal mol- higher in energy. Rotation
about the vinylic C-C bond is, however, fully possible at
ambient temperatures. Calculations show furthermore that
the potential curve for libration of the C=C-C-H dihedral
angle q5 is initially flat and increases more steeply only at
4 > 35". An evaluation of about 50 crystal structures of natural substances and synthetic products with the structural
element 24 shows, in agreement with this, that the dihedral
angles are uniformly distributed in the range 0-30". In individual cases values of 40" were obtained, but dihedral angles
greater than 44" were not found. If the n bond in 24 is part
of an aromatic system, as in 25, then somewhat larger dihedral angles may be tolerated on account of the longer C=C
bond. Values up to 48" have been found.[38.521
The partial structure 24 is thus a conformationally flexible
element, which exists in a preferred conformation that always produces a bend in the main chain. The resulting
1128
Fig. 4. Crystal structure of l'kpi-stegobinone (27).
d
The configurational change in the transition from 26 to 27
appears at first glance to be only minor. Yet because of the
ally1 system, the spatial arrangement of the side chain[55]is
completely different in the two e p i m e r ~ . ' ~2-Substituted
~]
vinyl units located in equatorial positions of six-membered
rings, as in 28, often serve to fix large structural units in
natural products in an energetically preferred, spatial arrangement. Such a structural unit is found for example in
RZ
H
28
FK 506
29
FK 506 (29).1"' In 28 the orientations of the substituents on
the vinyl group as well as those of all the bonds about the
six-membered ring are set by the single preferred conformation of this structural unit.
Angew. Chem. Iiit. Ed. Engl. 1992, 31, 1124-1134
(Fig. 6).[59' One can follow through segment by segment in
this structure how the substituents arranged in this particular way favor just the one conformation found in the X-ray
crystal structure. Despite total conformational mobility, this
conformation causes a 180" bend in the molecular backbone.
The phenomenon of allylic 1,3 strain was originally recognized in compounds of type 30.[501Here, the ring substituent
R prefers to adopt the axial position because of the Z orientation of the substituent RZ.This also applies to amides of
the type 31, due to the double-bond character of the N-CO
bond.[581It has been known and understood for a long time
that a ring substituent in the 2 position of N-acylpiperidines
31 preferentially adopts an axial arrangement, even if this is
offset by a 1,3-diaxial interaction.
H
P
Ph
Nature utilizes this effect, as can be seen by a glance at the
crystal structure of FK506 (29) (Fig. 5). The COOR substituent on the piperidine ring of 29 is axial, and oriented
analogously to that in conformation 31b. A combination of
Fig. 6. Crystal structure of the antibiotic M139603 (32)as a 4-bromo-3.5-dinitrobenzoate. The conformation is determined by allylic 1.3 strain and the avoidance of g'g- interactions (CH, groups).
4. Conformational Design of Molecular Skeletons
0
Fig. 5. Crystal structure of FK506 (29). The COOR substituent on the piperidine ring is in the otherwise energetically unfavorable axial position, in order to
minimize interactions with the N-acyl substituent.
conformational control by allylic 1,3 strain with that produced by methyl substituents (avoidance of g'g- interactions) is found for example in the antibiotic MI39603 (32)
M 139603 32
Angeiv. Clirrn. Int. Ed. Engl. 1992, 31, 1124-1134
The goal of molecular design nowadays is frequently the
synthesis of a complementary molecule for a receptor, so
that this molecule exhibits specific functionalities in a spatial
arrangement suitable for binding to the receptor. One of the
problems in this connection i s finding an appropriate molecular skeleton on which the bonds to the functional groups,
for example to a C-NH, or C-COOH group (see33), not
only have the correct spacing but are also vectorially in the
correct spatial orientation. The program CAVEAT, developed by P. A. Bartlett et a1.r601(Berkeley) for this purpose,
searches all structures stored in the Cambridge Structural
Data File for a matching molecular skeleton. In this search
it is irrelevant whether the molecular skeleton i s rigid or
flexible. A recent survey of peptide conformation mimetics[6'1shows that up to now mainly rigid molecular skeletons
have been tested in order to simulate, for example, a bend in
a peptide chain corresponding to a fi turn @-turn mimetics).
An attempt could also be made in this context to connect
the necessary functionalities with one another by means of a
section from a diamond lattice. Assuming that this would be
possible with sufficient spatial agreement, one could design
a rigid, polycyclic molecule that would inevitably produce
the necessary arrangement of the functional groups in space.
By omitting individual skeleton bonds one by one, one
would eventually reach the other extreme, namely a completely flexible chain-type molecule, which could of course
adopt the desired conformation, but only as one of an almost
infinite number of possibilities. The intellectual challenge
now is to design, with the aid of principles illustrated in
nature or developed by insight and intuition, a completely or
overwhelmingly flexible molecular skeleton, which neverthe1129
less has the desired conformation as its preferred conformation. For example, the recently described[621antagonist 34 of
N-methyl-D-aspartate exhibits (accidentally or intentionally)
just such properties, since in 34 the allylic 1,3 strain ensures
a specific preferred conformation of the molecular skeleton.
n
HO
34
COOH
H2Nb
NH
\
35
Likewise, the nitro group in the ortho position of the phenyl
substituent in nifedipin (35)ensures, due to allylic 1,3 strain,
that the phenyl ring is orthogonal to the dihydropyridine
ring, an arrangement which is decisive for the pharmacological effe~t.1~~1
4.1. Design of Preferred Conformations of a C, Chain;
Flexible Building Blocks for Conformational Design
of a central tt, tg', or gig+ unit are shown in separate
groups. It becomes apparent that derivatives of spirodiadamantane may serve as rigid models for the conformers of
n-heptane when a correct spatial arrangement of functional
groups along a heptane chain is required.
In addition to the two extreme cases, namely the conformationally fully flexible n-heptane of unspecified shape on
the one hand, and the completely rigid spirodiadamantane
derivative with a fixed, defined shape on the other hand,
flexible n-heptane skeletons with a defined shape should be
able to be constructed according to the principles illustrated
by nature (avoidance of g'g- interactions). In a first stage
the problem can be simplified by fusing a six-membered ring
to the C, chain. One or two dihedral angles can thus be set
in a preferred Conformation. Conformational mobility is retained, although restricted, about these intraring bonds as a
consequence of the inversion of the six-membered ring,
which is in full operation at ambient temperatures. With the
fusion of a six-membered ring to the two internal bonds of
n-heptane, a 1,3 diequatorial arrangement of substituents on
the cyclohexane ring corresponds to a central it conformation, and a l ,3 equatorial-axial arrangement to a central tg
conformation. If further auxiliary substituents are attached
to the ring or to positions 2 and 5 on the chain, any of the
four arrangements of a C, chain with a central tt unit, or any
of the six arrangements with a central tg unit can be rendered
to be the preferred conformation (Scheme 5). Calculations
with MACROMODEL[661show that the conformation
sought in each case should be populated predominantly.
The chemist will be inclined to tackle a complex problem
in conformational design stepwise, that is, by considering
skeletal segments with specific preferred conformations.
These segments could then be assembled like building blocks
tttt
to form larger, realistic molecular skeletons. One could, for
example, consider the C, chain of n-heptane as a skeletal
95 %
segment which is long enough to illustrate repeatable units.
The conformation of n-heptane can be described by a sequence of four dihedral angles. The 13 conformations that
are free of g+g- interactions (see ref.['71), as well as those
with a partially relaxed g'g- interaction are all populated at
room temperature.
g+ t tg+
The conformations of n-heptane without g'g- interactions can now be depicted on a diamond l a t t i ~ e . [ ~ ~ . ~ ~ ] 88%
Scheme 4 illustrates this on the basis of the molecular skeleton of spirodiadamantane. Those conformations composed
tttt
ttrgg- t tggttg+
ttg't
its's'
g-tg+t
9- tg+9'
g+ tg' t
9' tg+g+
Scheme 4. Conformations of n-heptane without g+g- interactions superimposed on a diamond lattice.
1130
g-tg-t
95 %
'
g+ttt
77 Yo
'
g+ttg-
g-ttg'
83%
83 %
tg-tt
44 %
83 %
44%
& &
g-tg-r
89 %
Scheme 5. Fusion of a six-membered ring to n-heptane. The 1,3 diequatorial
orientation of the substituents on the cyclohexane ring corresponds to a f f
conformation on the internal bonds of n-heptane, the 1,3 equatorial-axial orientation to a tg conformation.
Angew. Chem. Int. Ed. Engl. 1992, 31, 1124-1134
Of course, one or both of the outer dihedral angles of the
heptane chain can also be fixed in specific preferred conformations by ring fusion. For example, 36 corresponds to a
chain with g +ttg+ conformation.
Without altering the conformational preference, two further methyl (alkyl) groups may be placed in a strategically
correct manner on 36. In the resultant compound 37, 13 of
the regular conformations of n-heptane can be superimposed
onto the preferred conformation 37 a. The skeleton 37 thus
offers numerous possibilities for spatially stabilizing specific
heptane conformations, and this with unrestricted conformational mobility.
A gem-dialkyl substitution offers a further starting point
for the conformational fixing of a heptane chain, for example at C4 in 38. As Alder et al.[671have pointed out, this
means in the first place that the two outer dihedral angles of
the C, chain prefer a t conformation (MACROMODEL
calculations show a ca. 86% preference for a t conformation). Further methyl substituents, for example in 41, favor
the ttgt arrangement 41 a (74%). The isomer 42 on the other
hand has, according to MACROMODEL calculations, two
sets of similar, roughly equally populated conformations,
namely the tttt arrangement 42a and the tg-g-t arrangement 42 b.
r tg't
ttrt
rg-gr
If it is desired to model a heptane chain with a central
g + g + (or g-g-) conformation, the two geminal methyl
groups can be replaced by a six-membered ring, as in 39. A
g conformation is thereby imposed on one of the internal
Angew. Chem. I n r . Ed. Engl. 1992, 31, 1124-1134
bonds of the heptane chain. On account of the rapid inversion of the six-membered ring, a g conformation is then
effectively preferred for both internal heptane bonds, that is,
molecule 39 should exist mainly in the tg+g+tconformation
(or the enantiomeric tg-g-t conformation). This can then be
achieved completely by turning to the adamantane derivative 40. This is a remarkable molecule: on the one hand
rotation about all the bonds of the heptane chain is unrestricted, while on the other hand 40 has only one pair of
enantiomeric preferred conformations !
The structures shown here model 11 of the 13 regular
conformations of an n-heptane chain without g + g - interactions, such that the desired conformation is the preferred
conformation with total or substantial preservation of the
conformational mobility.
While as a rule g+g- conformations are energetically unfavorable if population of such a conformation chain is desired, this can be achieved by the introduction of a tert-butyl
substituent on the chain. The molecule 43 might well exist to
a large extent in the conformations 43 a and 43 b, which both
exhibit a syn-pentane interaction.
According to DeClercq et a1.[681this "tert-butyl anchoring"
is one way of populating the otherwise unfavorable g+gconformation of a chain, so that ring-closing reactions of the
chain ends are favored.
4.2. Applications of Conformational Design
The shape of a molecule and the associated spatial arrangement of functional groups are particularly important
when the molecule is to be bound to another molecule or to
ions. For this reason conformational design is currently used
primarily in the development of host molecules for ions or
amino acids.
Ligand conformation is particularly important in the development of optimum polydentate ligands. The coordination of the ligand is most favorable when its ground-state
conformation resembles that in the complex. This can be
achieved, for example, by suitably located methyl substituents.
Such conformational design was demonstrated by Still
et
par excellence in the case of a polyether chain.
Polyethers have many acceptor positions for hydrogen
bonds; they thus have a marked tendency to complex ammonium ions. The polyether 44 may well prefer the tg+ttg+ttgf
helical arrangement, which predominates in polyethyleneglycol derivatives,[701though of course only as one of many
other possible conformations. The fusion of six-membered
rings as in form 45 specifies in each case two successive t
arrangements of the main polyether chain. The resulting
t?tt?tt? sequence still permits 25 conformations which are up
to 3 kcal mol- ' higher in energy than the most stable conformation. Only when further methyl substituents are intro1131
duced, as in 46, is a molecule attained with only a single
low-energy conformation, since all other conformations
have destabilizing gtg- interactions. We are thus dealing
with a conformationally fully flexible molecule, which nevertheless has only a single helical designer conformation
(g+ttg-ttg'). As a consequence, 46 exhibits a substantially
higher enantioselective recognition of protected amino acids
than 45.r6937 ' 1
44
45
46
A further example of such a ligand design is provided by
a [14]thiacrown-4 for complexing Niz+ (Fig. 7).1721By means
of a geminal dimethyl substitution on the macrocycle 47, a
trans conformation of the CC-SC bond in 49 is induced
which is also found in complex 48. The binding constant for
Ni2+increases correspondingly by a factor of 50 in the transition from the ligand 47 to 49.t72J
The control of conformer populations by means of avoidance of g+g- interactions is just one of the principles that
can be applied in conformational design. Flexible structural
elements whose shape is determined by allylic 1,3 strain or by
the conformational preferences of an amide or urea group,1751
may also be used.
A timely problem is the design and synthesis of chiral
ligands for metal-catalyzed reactions. For example, the easily accessible complex 52 would have the disadvantage that
the phenyl and methyl groups on the ligand, which should be
responsible for asymmetric induction, are not spatially fixed.
In other words, many conformations are possible regarding
rotation about the indicated bonds. This disadvantage is
avoided in the complex 53,[761
since allylic 1,3 strain specifically fixes the phenyl and methyl groups in the ligand to
produce a defined chiral environment at the metal center.
47
48
5. Summary and Future Prospects
The spatial structure of many polyketide natural substances
illustrates the principles that nature employs to impart a
defined shape to these molecules while largely retaining conformational flexibility. These principles can be utilized as such
or developed further in order to confer by structural modifi49
49'
Fig. 7. Crystal structures of the [14]thiacrown-4 macrocycles 47 and 49 as well
as their respective complexes which form upon addition of Ni2+,48 and 4 9 .
Hatched spheres are Ni atoms, dotted spheres S atoms.
R
54
Molecules with a boomerang shape could also be tailormade. For example, compound 51 should-by analogy to
the investigations carried out by Vogtle et a1.[731on 5&be
even better able to bind thiourea than 50 since the host
molecule 51 should spontaneously adopt the optimum conformation for bonding.[741
1132
55
56
Artgew. Chern. Int. Ed. Engl. 1992, 31, 1124-1134
cation a definite preferred conformation on a molecular
chain (conformational design). If, for example, it is desired
to produce a rod-shaped flexible molecule, structures 54 to
56 could be sought.
In the syntheses of such compounds with fairly short
chains the problem would be primarily that of stereoselectivity, while in the syntheses of those with longer chains it
would that of stereoregular polymerization.[771
If on the other hand it is desired to construct helical molecular chains, one could seek a steep helix through a
tg+(tg+),tg+sequence, as in 57. This would be an isotactic
polypropylene reinforced in its conformational preference.
A flatter helix would result from a ttgC(ttgC),ttgcconformation (cf. ref.[”I). This could be achieved for example with
a structure such as 58.
The examples given above are obvious solutions, though
certainly not the only and perhaps also not the best solutions
for the design problems presented. It is clear, however, that
high demands will be placed on the art of stereoselective
synthesis when such molecules are synthesized. In view of the
breathtaking developments in methods and procedures of
stereoselective synthesis over the last 15 years, it may be
hoped that molecules such as 56 or 57 will soon no longer
present insuperable synthetic problems. With further progress in synthesis, efficient conformational design will be
able to be performed not only on the computer screen but
also in the laboratory as a matter of routine. One will then
also be able to answer the question of whether conformationally flexible, biologically active substances hitherto employed by nature have advantages over conformationally
rigid, biologically active substances.
The review does not aim to, and certainly is not able to,
deal exhaustively with all the possibilities in the conformational design of molecular skeletons. It should, however,
indicate above all the relevant principles and provide a stimulus for further thought.
I wish to thank M . Brumm and Dr. 7: Sander, Marburg,
(FRG), for the results of MACROMODEL calculations reproduced herein. Z also wish to thank Prof. G. Frenking, Marburg, for advice regarding technical details.
Received: February 14,1992 [A 878 IE]
German version: Angew. Chem. 1992, 104, 1147
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1133
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