Synthesis of novel polyethers in a geometrically precise conformation

Article abstract of DOI:10.1021/ol990618h

Formula presented A convergent design for the preparation of a polyoxyethylene-based channel molecule is presented, and the synthesis of the key unit 2 required for the projected construction is described. The essential elements of the design included fac

Full text of DOI:10.1021/ol990618h

ORGANIC
LETTERS
1
999
Vol. 1, No. 5
25-728
Synthesis of Novel Polyethers in a
Geometrically Precise Conformation
7
Rosa M. Rodr ´ı guez, Ezequiel Q. Morales, Mercedes Delgado,
Carmen G. Esp ´ı nola, Eleuterio Alvarez, Ricardo P e´ rez, and Julio D. Mart ´ı n*
Instituto de InVestigaciones Qu ´ı micas, CSIC, Am e´ rico Vespucio, s/n,
Isla de la Cartuja, 41092 SeVille, Spain
jdelgado@cica.es
Received April 27, 1999
ABSTRACT
A convergent design for the preparation of a polyoxyethylene-based channel molecule is presented, and the synthesis of the key unit 2
required for the projected construction is described. The essential elements of the design included face to face oriented macrorings spaced
by rigid trans-fused oxanes. The strategy combines conformational predictability of C-linked oxanyl systems and ring-closing metathesis for
the synthesis of crown ethers with engineerable ion-binding abilities.
Effective conformation design to attain a monoconforma-
tional situation in large polyoxyethylene backbones would
offer a good strategy for selective cation transport. In our
unimolecular model 1, the essential elements of the design
included face to face oriented cyclic ethers spaced by rigid
trans-fused oxacycles.
1
,2
(1) Incorporation of macromolecular polyether derivatives into lipids has
been shown to result in cation transport rates comparable to those ion
channels formed by natural and synthetic oligopeptides or antifungal
macrolides: (a) Fyles, T. M.; Loock, D.; Zhou, X. J. Am. Chem. Soc. 1998,
1
1
20, 2997-3003. (b) Meillon, J.-C.; Voyer, N. Angew. Chem., Int. Ed. Engl.
997, 36, 967-968. (c) Pechulis, A. D.; Thompson, R. J.; Fojtik, J. P.;
Schwartz, H. M.; Lisek, C. A.; Frye, L. L. Bioorg. Med. Chem. 1997, 5,
1
893-1901. (d) Maguire, G. E. M.; Meadows, E. S.; Murray, C. L.; Gokel,
G. W. Tetrahedron Lett. 1997, 38, 6339-6342. (e) Abel, E.; Meadows, E.
S.; Suzuki, I.; Jin, T.; Gokel, G. W. J. Chem. Soc., Chem. Commun. 1997,
1
145-1146. (f) Murray, C. L.; Meadows, E. S.; Murillo, O.; Gokel, G. W.
J. Am. Chem. Soc. 1997, 119, 7887-7888. (g) Murillo, O.; Suzuki, I.; Abel,
E.; Murray, C. L.; Meadows, E. S.; Jin, T.; Gokel, G. W. J. Am. Chem.
Soc. 1997, 119, 5540-5549. (h) Wagner, H.; Harms, K.; Koert, U.; Meder,
S.; Boheim, G. Angew. Chem. 1996, 108, 2836-2839; Angew. Chem., Int.
Ed. Engl. 1996, 35, 2643-2646. (i) Stadler, E.; Dedek, P.; Yamashita, K.;
Regen, S. L. J. Am. Chem. Soc. 1994, 116, 6677-6682.
(
2) Remarkably, the recently reported crystal structure of the potassium
+
ion (K ) channel reveals that the main chain atoms create a structurally
constrained stack of oxygen atoms that tightly coordinate K ions but not
smaller Na ions: (a) Doyle, D. A.; Morais-Cabral, J.; Pfuetzner, R. A.;
Kuo, A.; Gulbis, J. M.; Cohen, S. L.; Chait, B. T.; MacKinnon, R. Science
3
Here, as a first step toward the synthesis of 1, we describe
+
+
the synthesis of the oxane-linked subunit 2 and report on its
4
conformational behavior.
1
998, 280, 69-77. (b) MacKinnon, R.; Cohen, S. L.; Kuo, A.; Lee, A.;
The purpose of the present communication is also to show
how our model may be applied to simulate the dynamics of
Chait, B. T. Science 1998, 280, 106-109. (c) Kreusch, A.; Pfaffinger, P.
J.; Stevens, C. F.; Choe, S. Nature 1998, 392, 945-948.
1
0.1021/ol990618h CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/12/1999

channel organization. The strategy for the synthesis of 2 is
outlined in Scheme 1.
spiroacetal 5. This latter system was envisioned to arise via
the acetylene 6 by partial reduction to the cis-olefin and
spirocyclization.
6
Both precursors, dibromoolefin 7 and lactone 8, can be
7
readily prepared from 9 by standard methodologies (Scheme
Scheme 1. Retrosynthesis of the Tetracyclic Polyether 2
2). Coupling of lactone 8 with the acetylene anion generated
in situ from dibromide 7 gave the hemiacetal 21, which was
further treated with CSA/MeOH to produce the acetal 6 (62%
yield, over two steps). Partial hydrogenation of 6 and
treatment of the resulting olefin with BF
3
2
‚Et O/MeCN gave
8
the spiroketal 23 (84% yield), which was then oxidized with
9
TPAP-NMO (for abbreviations see ref 23) to furnish ketone
5
(88% yield). Reduction of 5 using BF
resulted in the desired diol 4 (R ) H) (84% yield).
Compound 3 was prepared in 64% yield by treatment of 4
R ) H) with t-BuOK (2.2 equiv) and excess allyl diethylene
glycol toluene-p-sulfonate in THF at 25 °C. Finally, reaction
in CH Cl (0.005 M) with 10 mol % of bis(tricyclohexyl-
3
‚Et
2 3
O and Et SiH
10
(
3
2
2
phosphine)benzylideneruthenium dichloride, at 25 °C for 5
5
h, provided 81% of the macrocycle 2.
We have studied the conformational behavior of 4 (R )
Ac) by NMR methods coupled with force-field computa-
1
1,12
1
1
tion.
Averaged H- H coupling constants over the
1
3
calculated whole set of conformers gave a 500 MHz
simulated H NMR spectrum fully in agreement with the
experimental one. Calculated interproton distances obtained
from 2D-NOESY and those corresponding to each con-
former exhibit a very good agreement, showing that, in
solution, 93% of the conformer population is covered by two
major conformations: R ) â ) γ ) 180° (66%, 86%, and
1
14
1
5
8
0%, respectively) and R ) 55° (18%), â ) γ ) 180° (86%
and 80%).
(6) For a different approach to the synthesis of lactone 8, see: Zheng,
W.; De Mattei, J. A.; Wu, J.-P.; Duan, J. J.-W.; Cook, L. R.; Oinuma, H.;
Kishi, Y. J. Am. Chem. Soc. 1996, 118, 7946-7968.
(7) Compound 9 was prepared from triacetyl-D-glucal according to the
described procedure: Nicolaou, K. C.; Hwang, C.-K.; Marron, B. E.; De
Frees, S. A.; Coulados, E. A.; Abe, Y.; Carroll, P. J.; Snyder, J. P. J. Am.
Chem. Soc. 1990, 112, 3040-3054.
(8) The exclusive selection of one of the possible conformations for
spiroacetal 23 is a consequence of the stabilizing anomeric and exo-anomeric
effects that direct both C-O bonds to axial positions on the respective rings.
For a review, see: Perron, F.; Albizati, K. J. Chem. ReV. 1989, 89, 1617-
It was anticipated that the macrocyclic ring in 2 could be
obtained by ring-closing metathesis (RCM) of the bis(allyl)
5
1661.
podand 3 derived from the basic diol 4 (R ) H), which in
turn could be obtained by silane double reduction of the
(9) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
994, 639-666.
10) Applications involving reductive cleavage of the anomeric center
1
(
in spiroacetals have only recently been recognized for their potential
synthetic utility. For recent examples, see: (a) Crimmins, M. T.; Rafferty,
S. W. Tetrahedron Lett. 1996, 32, 5649-5652. (b) Oikawa, M.; Veno, T.;
Oikawa, H.; Ichihara, A. J. Org. Chem. 1995, 60, 5048-5068.
(11) This is done by minimizing the individual structures by an MM3*
force field implemented in the MacroModel V6.0 program. Mohamadi, F.;
Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Lipton, M.; Caulfield, C.;
Chang, G.; Hendrikson, T.; Still, W. C. J. Comput. Chem. 1990, 11, 440-
447.
(12) Calculated coupling constants for diacetate 4 (R ) Ac) gave better
agreement with the experimental values than did those constants for free
hydroxyl groups: Haasnot, C. A. G.; De Leeuw, F. A. M.; Altona, C.
Tetrahedron 1980, 36, 2783-2792.
(13) Monte Carlo calculations were made, yielding a set of 192
conformers (see the Supporting Information).
(
3) Reviews related to synthetic models for transmembrane channels:
(
a) Gokel, G. W.; Murillo, O. Acc. Chem. Res. 1996, 29, 425-432. (b)
Fyles, T. M.; Straaten-Nijenhuis, W. F. In ComprehensiVe Supramolecular
Chemistry; Atwood, J. L., Davies, J. E. D., MacNichol, D. D., V o¨ gtle, F.,
Reinhoudt, D. N., Eds.; Pergamon: Oxford, U.K., 1996; Vol. 10, pp 53-
7
7. (c) Voyer, N. Top. Curr. Chem. 1996, 184, 1-37. (d) Akerfeldt, K. S.;
Lear, J. D.; Wasserman, Z. R.; Chung, L. A.; DeGrado, W. F. Acc. Chem.
Res. 1993, 26, 191-197.
(4) The reason for using crown ether homologues as the pore-forming
moieties is the fact that their binding ability can be engineered to specific
needs. Thus, the cavity diameter 5.5(5.9)-7.8(7.6) Å of the selected
macroring in 2 and its weaker binding efficiency in comparison with 18-
crown-6 analogues (see the Supporting Information) should allow for the
transport of a wide variety of metal ions.
(
5) (a) K o¨ ning, B.; Horn, C. Synlett 1996, 1013-1014. (b) Marsella, M.
(14) Simulations were done using gNMR 6.3.5 from Cherwell Scientific
Publishing Ltd., The Magdalen Centre, Oxford Science Park, Oxford OX4
4GA, U.K.
(15) Analysis of the spectra were made using TRIAD 6.3 as part of the
package SYBYL 6.3 from Tripos Inc. (Supporting Information).
J.; Maynard, H. D.; Grubbs, R. H. Angew. Chem., Int. Ed. Engl. 1997, 36,
1
101-1103. (c) Mohr, B.; Weck, M.; Sauvege, J.-P.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1308-1310. (d) Delgado, M.; Mart ´ı n, J.
D. Tetrahedron Lett. 1997, 38, 8387-8390.
726
Org. Lett., Vol. 1, No. 5, 1999

Scheme 2. Synthesis of the Tetracyclic Polyether 2a
a
Reagents and conditions: (a) 5.0 equiv of SO
.0 equiv of CBr , CH Cl , 0 °C, 20 min, 83%; (c) 2.0 equiv of n-BuLi, THF, -78 °C, 20 min, then H
THF, 0 °C, 12 h, then 10 equiv of 3 N NaOH, 20 equiv of 30% H , 0 °C, 2 h, 88%; (e) 1.3 equiv of NaH, 1.2 equiv of (MeO)
CO Me, benzene, 25 °C, 15 min, then add 11, 25 °C, 15 min, 88%; (f) 5.0 equiv of DIBALH, Et O, 0 °C, 1 h; quench with NaOH-H
8%; (g) 0.3 equiv of Ti(O-i-Pr) , 0.4 equiv of (+)-diethyl tartrate, 1.8 equiv of t-BuOOH (5-6 N in decane), 4 Å MS, CH Cl , -20 °C,
2 h, 95%; (h) 1.1 equiv of TsCl, 0.05 equiv of 4-DMAP, 2.5 equiv of Et N, CH Cl , 25 °C, 8 h, 93%; (i) 2.3 equiv of NaI, 2.0 equiv of
, butanone, 60 °C, 1 h, 97%; (j) 2.0 equiv of t-BuLi, Et O, -78 °C, 2 h, 99%; (k) 2.0 equiv of MEMCl, 4.0 equiv of (i-Pr) EtN,
.1 equiv of 4-DMAP, CH Cl , 25 °C, 5 h, 95%; (l) (i) 3.0 equiv of NMO, OsO catalyst, THF-H O-acetone (1:1:1), 25 °C, 12 h, 75%,
ii) 1.2 equiv of TBAF, THF, 25 °C, 6 h, (iii) 2.5 equiv of (n-Bu) NIO , MeOH-H O (4:1), 20 °C, 3 h, 81% for two steps; (m) 1.5 equiv
of PCC, 0.2 equiv of NaOAc, CH Cl , 25 °C, 12 h, 66%; (n) 2.0 equiv of n-BuLi, THF, -78 °C, then add 1.0 equiv of 7, -78 to 0 °C,
then add 1.0 equiv of 8, -35 °C, 30 min, 77%; (o) 0.2 equiv of CSA, MeOH, 25 °C, 24 h, 80%; (p) 10 wt % of 10% Pd-CaCO , 0.07
equiv of quinoline, H , EtOAc, 25 °C, 10 h, 95%; (q) 1.1 equiv of BF ‚Et O, MeCN, -30 °C, 20 min, 88%; (r) 0.1 equiv of TPAP, 1.5
equiv of NMO, CH Cl , 25 °C, 2 h, 88%; (s) 8.0 equiv of Et SiH, 5.0 equiv of BF ‚Et O, MeCN, -15 °C, 20 min, 84%; (t) 2.2 equiv of
allyl diethylene glycol toluene-p-sulfonate, 2.2 equiv of t-BuOK, THF, 50 °C, 4 h, 64%; (u) 3, 0.005 M in CH Cl , 10 mol % [(PCy
RuCHPh]Cl , 25 °C, 12 h, 81%. For abbreviations see ref 23.
3
‚pyr, 5.0 equiv of Et
3
N, CH
2
Cl
2
-DMSO (6:1), 25 °C, 4 h, 75%; (b) 4.0 equiv of Ph
O, 82%; (d) 2.0 equiv of (Sia) BH,
POCH
O,
3
P,
2
4
2
2
2
2
O
2 2
2
2
-
2
2
2
9
1
4
2
2
3
2
2
NaHCO
3
2
2
0
(
2
2
4
2
4
4
2
2
2
3
2
3
2
2
2
3
3
2
2
2
3 2
) -
2
Since the conformational behavior of cyclized ether 2 is
simulated three-unit oligomer, using a continuum solvent
model. In the model ꢀ ) 4.0 (CHCl ), which is the one
expected to simulate the interior environment of mem-
16
identical with that of the acyclic precursor 3, we can expect
mid-plane oxane systems in 2 to be perpendicular to the ring
plane of the crown ether moiety, a situation which is ideal
3
17
(20) HOLE suite of programs. Smart, O. S.; Goodfellow, J. M.; Wallace,
for channel formation (Figure 1). Molecular dynamic
B. A. Biophys. J. 1993, 65, 2455-2460.
studies were carried out over the macrocyclic unit 2 and a
(21) Calculations were done by fixing the backbone of the oligomer,
allowing only the movement of the atoms forming the cyclic ether ring.
MMFF 94 was used with our standard conditions (Supporting Information).
(
16) The NMR characteristic observed for 2 and 3 were virtually
superimposable on those of the relevant protons and carbons.
17) As is the case for all ring-forming reactions, the RCM of polyoxy-
(
22) The analogue 2i, conveniently functionalized for coupling reactions
following the synthetic sequence described in Scheme 1, has been prepared
to be submitted for publication):
(
(
ethylene rings is determined by several factors, including the kinetics of
ring closing, ring strain, and competing metathesis-based polymerization.
In the case of compound 3 (2R,3S,2′R,2′′S,4′′aR,8′′aS) the RCM to give 2
occurs due to the favored preorganization of the C-linked oxanyl system,
which allows close proximity of the terminal olefins. All attempts to prepare
diastereomers of 2 by RCM of diastereomers of 3, 3a (2R,3S,2′S,2′′S,
4′′aR,8′′aS), 3b (2S,3R,2′R,2′′S,4′′aR,8′′aS), and 3c (2S,3R,2′S,2′′S,4′′aR,8′′aS),
were unsuccessful. This gathered information was of crucial importance in
the selection of the target unit subject of the present communication.
(
18) Coveney, P. V.; Emerton, A. N.; Boghosian, B. M. J. Am. Chem.
Soc. 1996, 118, 10719-10724.
19) Although this computer modeling was the basis for the selection of
(
the “building block” 2, rigorous testing will be required to determine whether
the design lives up to its expectations as an ion channel agent.
Org. Lett., Vol. 1, No. 5, 1999
727

Figure 1. Preferred solution conformation of 4 (R ) Ac) (top)
and 2 (bottom). Monte Carlo studies in conjunction with distance
calculations, from 2D-NOESY NMR experiments, over the A-B-C
unit give us the two preferred conformers 2A and 2B, covering
88% of the overall population.
branes,18 100% of the sampled structures have R ) â ) γ
180° conformation. This simulated model localizes crown
ether residues face to face on the same side of the mid-plane
Figure 2. 3-D representation and HOLE analysis of the three
A-B-C unit oligomer: (a, left) extended projection of the three-
unit oligomer of 2, generated by MD studies using a continuum
)
solvent model with ꢀ ) 4.0 (CHCl ), 100%, R ) â ) γ ) 180°;
3
which contains the oxanyl system, forming a channel for
(b, right) HOLE surface of the inside of the channel (red, diameter
less than 1.15 Å; green, diameter between 1.15 and 2.3 Å; blue,
diameter larger than 2.3 Å).
ions long enough (40 Å) to span a bilayer membrane, as
illustrated in Figure 2 (left).19
A HOLE study of such channels shows the internal surface
20
of the pore (Figure 2, right). For this conformation,
prediction of the conductance was carried out using the same
suite of programs, combining the conductances of the
individual rings. The expected conductance, in any case, is
about 20 pS in 1 M KCl, about one-third that of gramicidin.
However, calculations of the pore diameter after an MD run
Acknowledgment. The financial support of the MEC
(Grant No. PB97-1123) of Spain and the Ram o´ n Areces
Foundation is gratefully acknowledged. E.Q.M. and M.D.
thank the MEC of Spain for a fellowship. We also acknowl-
edge P. Nieto, from the Instituto de Investigaciones Qu ´ı mi-
cas, for helpful discussions on NMR and O. Smart for his
help in using HOLE.
21
of 100 ps shows that it ranges from 0.5 to 2.5 Å, allowing
possible cation transfer through the membrane. Work is
22
currently under way to prepare oligomers of 2 and to
elucidate their transport abilities.
Supporting Information Available: Experimental details
and characterization data for compounds 2-23, NMR
studies, and calculation details. This material is available free
of charge via the Internet at http://pubs.acs.org.
(
23) Abbreviations: TBS ) tert-butyldimethylsilyl; MEM ) methoxy-
methyl; DMSO ) dimethyl sulfoxide; KHMDS ) potassium bis(trimeth-
ylsilyl)amide; DIBALH ) diisobutylaluminum hydride; MS ) molecular
sieves; 4-DMAP ) 4-(dimethylamino)pyridine; NMO ) 4-methylmorpho-
line N-oxide; TBAF ) tetra-n-butylammonium fluoride; PCC ) pyridinium
chlorochromate; CSA ) 10-camphorsulfonic acid; TPAP ) tetra-n-
propylammonium perruthenate.
OL990618H
728
Org. Lett., Vol. 1, No. 5, 1999