'As the births of living creatures at first are ill-shapen, so are all
Innovations, which are the births of time. Yet notwithstanding, as
those that first bring honour into their family are commonly more
worthy than most that succeed, so the first precedent (if it be good)
is seldom attained by imitation.'
Sir Francis Bacon, 1625
NEW DIRECTIONS IN DIMERIC SELF-ASSEMBLY
by
Christopher D. Bayne
Submitted to the Department of Chemistry on May 22, 1996 in partial
fulfillment for the requirements for the Degree of Master of Science in
Chemistry.
ABSTRACT
This report details the design and preliminary synthetic aspects of 'a new class of
molecules, which are expected to undergo dimeric self-assembly. Such molecules
contain a large degree of flexibility, unlike their well-studied rigid counterparts. Based
upon heteromacrocycles, these molecules are expected to undergo host-guest interactions
with metals as well as neutral guests. Recent advances regarding the synthesis and
detailed elaboration of glycoluril-based substrates are discussed. Additionally, a new
glycoluril-diene compound is introduced, and its synthesis is described.
Thesis Supervisor: Dr. Julius Rebek, Jr.
Title: Camille Dreyfus Professor of Chemistry
ACKNOWLEDGMENTS
Any scientist knows that the laboratory can be the coldest and darkest purgatory
imaginable when things are not going as they should. And God knows that this chemist
has experienced this feeling on a regular basis. People ask me why I come through that
door day after day with a smile on my face, and I usually can't tell them why - but I know
why. It's because of that certain 'atomosphere' which pervades our laboratory. This
'atomosphere' is replete of both camaraderie and scientific enthusiasm. It's just the way
that things should be. I want to acknowledge all of those individuals within the Rebek
Group who have made this feeling an integral part of our research. I cannot say enough
about the many, many people (literally everyone in the lab) who have so generously taken
the time to discuss chemistry with me in these many months. In my many experiences, I
have never seen such a brilliant group of young people interact so thoughtfully with one
another.
Thank you Dr. Rebek for making this atomosphere possible, and for your brilliant
inspirations and skillful leadership.
TABLE OF CONTENTS
ABSTRACT.....................................................................................................................
5
ACKNOW LEDGM ENTS...............................................................................................7
TABLE OF CONTENTS ........................................................................................
8
LIST OF SYNTHETIC SCHEM ES..............................................................................10
LIST OF FIGURES........................................................................................................11
Ch. 1................................................Introduction...........................................................15
1.1 A New Synthesis..........................................................................................15
1.2 Self-Assembly..............................................................................................16
1.3 Biological Self-Assembly............................................................................. 17
1.4 M etal-Directed Self-Assembly.....................................................................20
1.5 Hydrogen Bond-Directed Self-Assembly.....................................................23
1.6 Dimeric Self-Assembly through Hydrogen Bonds.......................................27
Ch.2.....................................................Design.................................................................30
2.1 Flexibility.....................................................................................................30
2.2 Thermodynamic Aspects of Flexibility........................................................31
2.3 Using M acrocycles to Explore Flexibility....................................................32
2.4 Implications of M etallic Host-Guest Interactions.........................................35
Ch.3....................................................Synthesis...............................................................36
3.1 Fragment Construction - Initial Glycoluril....................................................36
3.2 Fragment Construction - xa,c-Diolic Fragment.............................................38
3.3 Exploring Tetraester Cyclization M ethods....................................................42
3.4 Synthesis and Reactivity of an Improved Glycoluril Building Block............50
3.5 Functionalizations of the P,P3-bis(PM B) Diolic Fragment.............................54
3.6 Progress Towards a New Glycoluril-Diene Building Block..........................56
3.7 Remarks.........................................................................................................58
Ch.4...................................................Experimental.........................................................59
LIST OF SYNTHETIC SCHEMES
Scheme 1. General Alkyloxyaryl Glycoluril Synthesis...................................................37
Scheme 2. Synthesis of Boc-Protected Olefin Fragment.................................................38
Scheme 3. The cis-Dihydroxylation of the Olefin Fragment using OsO4.......................40
Scheme 4. An Alternative Route to the Desired Diol.....................................................41
Scheme 5. Failed Woodward-Pr6vost Reaction..............................................................41
Scheme 6. Attempts to Produce Tetraester Macrocycles using Stannoxanes.................43
Scheme 7. mono-Benzylation of Diacids using Tetrabutylammonium Fluoride............44
Scheme 8. Synthesis of P,4-Diacidic Fragment..............................................................44
Scheme 9. Cyclization Attempts using Acyl Halide Activation.....................................45
Scheme 10. Cyclization Attempts using Mixed Anhydride Activation...........................46
Scheme 11. A New Approach to Macrocycles via a Symmetric Anhydride....................47
Scheme 12. Synthesis of Diester/Diether Macrocycle.....................................................47
Scheme 13. mono-Protection using the TBDMS Group.................................................49
Scheme 14. mono-Protection, Fragment Coupling, and Deprotection using the TMS...50
Scheme 15. Glycoluril Condensations using p-Methoxybenzylurea...............................51
Scheme 16. Synthesis of PMB-Protected Glycoluril....................................................... 52
Scheme 17. bis(PMB)-Protected Glycoluril Substitution Reaction.................................52
Scheme 18. Woodward Reaction using bis(PMB) Olefinic Fragment............................53
Scheme 19. OsO4 Dihydroxylation using the bis(PMB) Olefinic Fragment....................53
Scheme 20. Functionalizations of the f,P-bis(PMB) Diolic Fragment Based on OSO4...54
Scheme 21. Functionalizations of the bis(PMB) Olefinic Fragment via Epoxidation......56
Scheme 22. Elimination Strategy using Vicinal Dihalide and DBU.................................57
Scheme 23. Production of Glycoluril-Diene Fragment Direction with NBS....................58
LIST OF FIGURES
Figure 1. Electron Micrograph of Viruses ......................................................................
16
Figure 2. Self-Assembly of Tobacco Mosaic Virus.......................................................18
Figure 3. A schematic representation of the process of protein folding.........................19
Figure 4. Self-Assembly of a metal chelate....................................................................20
Figure 5. Self-Assembly of a double-helical metal complex..........................................21
Figure 6. Self-Assembly of a G-Quartet.........................................................................22
Figure 7. The packing pattern between bis(acylamino)pyridines and diacids ................ 23
Figure 8. Cyclic trimerization of pyrido[4,3,-g]quinolinedione via hydrogen bonds.....24
Figure 9. The complex of cyanuric acid and melamine though hydrogen bonding........25
Figure 10. (1 + 3) Supramolecular complex....................................................................25
Figure 11. The chemical structure and resulting tubular assembly of a cyclic peptide....26
Figure 12. Self-Assembly of Self-Complementary molecules into 'tennis ball' ............... 27
Figure 13. Several self-complementary molecules having two-fold symmetry ................ 28
Figure 14. The jelly doughnut'......................................................................................... 29
Figure 15. Flexible 'softball' which was shown to collapse via intramolecular Bonds....30
Figure 16. Modular approaches to self-complementary macrocycles based on esters,
am ides, and im ines................................................................................32
Figure 17. The optimal sub-spacers for tetraester macrocycles based Molec. Modeling.33
Figure 18. Intramoleculular hydrogen bonding responsible for bending and/or twisting
in tetraam ides............................................................................................34
Figure 19. The malonaldehyde-based tetraimine macrocycle...........................................34
Figure 20. A tetraester macrocycle which is expected to readily complex certain
metals........................................................................................................
35
Figure 21. Vicinal coupling analysis.................................................................................40
Figure 22. Decomposition of deprotonated diol via 3-elimination...................................48
Figure 23. Asymmetric cyclization strategy......................................................................48
Figure 24. A new glycoluril-diene building block............................................................56
1. Introduction
1. Introduction
1.1 A New Synthesis
At the creative heart of all innovation is an inherent philosophy - a belief that if an
idea is imaginable, then it should be attainable through the methodical discovery and
creative application of new technologies.
It is this philosophy which has affected an
exponential growth in human scientific knowledge in the last three hundred years. This is
especially true in the sciences of biology and chemistry. Recently the 'melding' of these
two disciplines has led to greater insights into the microscopic inner workings of a most
important physical process - Life. There is an entirely new view of this process in light of
the realization that the information, which is responsible for this and most physical
phenomena, is stored at the molecular level. It is the translation of such information from
the chemical structure of individual molecules into the incredibly intricate physical
structures of life, via the seemingly trivial interactions between these molecules, which has
generated so much excitement among scientists of all fields in recent years.
Today scientists are imagining that, in the future, molecules will be designed with
the explicit purpose of performing various operations at the microscopic level. Tools will
be assembled at the molecular level from groups of identical molecules, which possess the
necessary information within their individual chemical structures to form architectures of
distinct size and shape.
Whereas traditional synthesis seeks to construct individual
molecules having known chemical makeup and arrangement through covalent bonds, this
new synthesis will seek to construct suprastructures of known size and shape through
noncovalent interactions from individual molecules, or groups of molecules.
Such
supramolecular synthesis is already well documented in nature in the form of various
complex biological structures. Among the simplest examples of such structures are the
simple viruses (Figure 1).
1. Introduction
Figure 1.Electron micrograph of a mixed preparation of Tobacco Mosaic Virus
(rod-shaped), the small spherical bacteriophage )X174, and the T4 phage.
1.2 Self-Assembly
Molecular self-assembly is the spontaneous association of molecules under
equilibrium conditions into stable, structurally well-defined aggregates connected through
noncovalent interactions or bonds. 1' 2 The information which determines the product of
such collective interactions is manifest in the orientation and properties of so-called
'complementary sites' within the individual molecules. It is via these sites that the
associations, which result through weak intermolecular attractions, produce aggregation.
The fields of molecular recognition and supramolecular chemistry are primarily
concerned with these noncovalent associations. 3
1 Whitesides, G. M.; Mathias, J. P.; Seto, C. T. Science 1991, 254, 1312-1319.
2For reviews of self-assembly, see:
Lindsey, J. S. New J. Chem. 1991, 15, 153-180. Lehn, J.M. Angew. Chem.
Int. Ed. Engl. 1990, 29, 1304-1319.
Kushner, D. J. BacterioL Rev. 1969, 33, 302-345. Bonar-Law, R.P.; Sanders,
J.K.M. TetrahedronLett. 1993,34, 1677-1680. Menger, F.M. Angew. Chem. Int. Ed. Engl. 1988, 27, 89-112.
3 Lehn, J.-M, ibid. 1988, 27, 89. Pedersen, C.J. ibid.. 1021. Cram, D.J. ibid., 1009. Diederich, F. ibid., 362.
Stoddart, J.F. Annu. Rep. Prog. Chem. Sect. B, 1989, 86, 353.
1. Introduction
The noncovalent interactions responsible for self-assembly vary widely in
character and strength. These include certain covalent bonds which can be formed and
broken
reversibly
(e.g.
disulfides),
inorganic
metal-ligand
bonds
(e.g.
salts,
organometallic complexes), hydrogen bonds, electrostatic interactions involving charges
(e.g. salt bridges in proteins) and dipoles (e.g. p-iodonitrobenzene 4), hydrophobic
interactions (e.g. micelles), aromatic n-stacking (e.g. nucleic acids) and charge transfer
complexes, as well as Van der Waals interactions.
generally
differentiated
directionality.
in terms
of their
These attractive interactions are
distance-dependence
(strength)
and
From these standpoints the hydrogen bond, which possess the most
reliable directional dependence, is the 'master key for molecular recognition'. 5 Studies
involving simple systems, which exploit such noncovalent interactions, have often been
designed to provide insight into the nature of biological self-assembly (such as the simple
viruses - Figure 1). Self-assembly is an inherent tendency in nature.
1.3 Biological Self-Assembly
The virtues of self-assembly emerged from reconstitution studies using viruses
such as the Tobacco Mosaic Virus (TMV). TMV (Figures 1 and 2) is composed of a
single strand of RNA (6400 nucleotides) enclosed within a protein layer which is 3000A
in length and 180A in diameter. The protein layer is formed from 2130 identical protein
monomers (Figure 2). It has been demonstrated 6 that this virus can be dissociated into its
component parts, and then reconstituted in vitro to re-form the intact virus.
This
experiment clearly demonstrated that all of the information necessary to faithfully
assemble the virus is built into its constituent monomers.
Pedireddi, V.R.; Sarma, J.A.R.P.; Desiraju, G.R., J. Chem. Soc. Perkin Trans. 2 1992, 311. Desiraju, G.R.; Pedireddi,
V.R.; Sarma, J.A.R.P.; Zacharias, D.E., Acta Chim. Hung. 1993, 130, 451.
5 Desiraju, G. R. Angew. Chem. Int. Ed. Engl. 1995, 34, 2311-2327.
6 Fraenkel-Conrat, H.; Williams, R.C.; Proc.Natl. Acad. Sci. U.S.A., 1955, 41, 690-698. Klug, A.; Angew. Chem. Int.
Ed. Engl., 1983, 22, 565-582.
4
1. Introduction
a
I
RNA
11;Z_
2130
Tobacco Mosaic Virus
Figure 2. Self-Assembly of Tobacco Mosaic Virus (TMV).
Certain concepts regarding the process of self-assembly emerged from these and
other biological studies in the area of self-assembly.7
First, in constructing large
biological structures, nature uses one or a few repeating subunits to greatly reduce the
amount of genetic information required. Second, using multiple, low-energy bonds to
associate subunits provides a means of controlling the self-assembly process (in both
directions) by changing various environmental factors. Next, self-assembly can be ea~rrorchecking since malformed or defective subunits (or associations) are unlikely to possess
the necessary bonding sites.
Finally, as in any process which involves repetitive
utilization of identical steps, this process is more efficient than comparable syntheses
using direct (covalent) construction.
Nature has mastered the art of integrating the weak non-covalent interactions
between individual chemical subunits to produce large suprastructures.
The primary
structures of enzymes contain the necessary information to accurately affect their folding
into defined secondary structures (Figure 3). These moieties, in turn, interact to form the
globular tertiary structures of proteins, which further assemble intermolecularly to form
7 Lindsey, J. S. NewJ. Chem. 1991, 15, 153-180.
SHopfinger, A.J.; Intermolecular Interactions in Biomolecular Organization; Wiley-Interscience: New
York, 1977. Hammes, G.B.; Enzyme Catalysts and Regulation; Academic: New York, 1982; Chapter 8.
Huang, C.Y.; Rhee, S.G.; Chock, P.B.; Ann. Rev. Biochem. 1982, 51, 935-971.
1. Introduction
the quartemary structures of enzymes. Thus, whereas subunits alone are incapable of
substrate recognition, collectively, they can catalyze transformations of enormous
complexity. 9 Other examples of biological suprastructures include various subcellular
structures,10 double-stranded DNA," tRNA molecules,'12 viruses 13, and many others.
U
2(
Figure 3. A schematic representation of the process of protein folding.
In recent decades chemists have tried to understand these phenomena by studying
novel suprastructures. It is the minimalist aspects of molecular recognition which have
interested researchers from the onset of these observations.
Specifically, science has
sought to understand the various devices of molecular recognition, whose inner-workings
make up the 'nuts and bolts' of the self-assembly process as a whole. Assemblies based
on hydrogen bonding and metal coordination have provided invaluable information
pertaining to the dynamics of molecular recognition and self-assembly, both in the liquid
and solid phases. Indeed our understanding of these interactions has beaconed the new
science of synthetic supramolecular chemistry. 14
9 Brandon, D.; Tooze, J.; Introduction to ProteinStructure; Garland Publishing: New York, 1991, Chapter
11. pp 161-176.
o10Alberts, B.; Bray, D.; Lewis, J.; Raff, M.; Roberts, K.; Watson, J.D.; Molecular
Biology of the Cell;
Garland Publishing: New York, 2nd Ed., 1989.
1" Cantor, C.R.; Schirranel, P.R.; Biophysical Chemistry Part III; Freeman: San francisco, 1980; pp 11091264.
12 Bogdanov, A.A.; Trends Biol. Sci 1989, 14, 505-507. Pleij, C.W.A. ibid. 1990, 15, 143-150. Draper,
D.E. Acc. Chem. Res. 1992, 25, 201-207.
13Kushner, D. J. Bacteriol. Rev. 1969, 33, 302-345. Brandon, D.; Tooze. J. The Structure of Spherical
Viruses;
Garland Publishing: New York, 1991; Chapter 11, pp 161-176.
14
For three ambitious papers which deal with supramolecular synthons in crystal engineering see: Desiraju,
G. R. Angew. Chem. Int. Ed. Engl. 1995, 34, 2311-2327.
M. C.Acc. Chem. Res. 1990, 23, 120-126.
Etter, M. C. J. Phys. Chem. 1991, 95, 4601-4610.
Etter,
1. Introduction
1.4 Metal-Directed Self-Assembly
One of the non-covalent interactions which has been commonly utilized by
researchers has been metal ligation. Metal chelates provide a means of imparting varying
degrees of pre-organization to ligands, which can possess much conformational flexibility
in their 'free' form. An example of this is the complexation of crown ethers with rareearth metals and transition metals (Figure 4).15
C(s)
C(S)
2.
C(Z)p
S-)4
A-N
-.
Ni
.r
&I
K,~)
p8 .NS.R
Moil
HC(15
SO)
(161
to)
C414)
(17)
at&NrSqR aNM
Figure 4. Self-Assembly of a metal chelate
A wealth of data concerning distinct interactions between metal ions and ligands
has been established within the fields of inorganic coordination and organometallic
chemistry.' 6 Such interactions, many of which are selective and reversible, are applicable
to self-assembly. Metal chelates, in fact, are highly employable for use in generating
supramolecular structures. More data are available concerning the roles of bonding and
structure (ring size and number, steric factors, ligand basicity, etc.) in determining chelate
stabilities than for any other self-assembling system.
Blake, A. J.; Reid, G.; Schroder, M. J. Chem. Soc., Dalton Trans. 1994, 22, 3291-3297
Saalfrank, R.W.; Stark, A.; Bremer, M.; Hummel, H.-U.; Angew. Chem. Int. Ed. Engl. 1990, 29, 311314. van Veggel, F. C. J. M.; Verboom, V.; Reinhoudt, D. N. Chem. Rev. 1994, 94, 279-299. Alexander,
V. Chem. Rev. 1995, 95, 273-342. Izatt, R. M.; Pawlak, D.; Bradshaw, J. S. Chem. Rev. 1995, 95, 25292586.
15
16
1.Introduction
1.
Inrodution21
12
CUM0
Figure 5. Self-Assembly of a double-helical metal complex. Two bipyridine strands (I)
and three copper(I) cations self-organize into a deoxyribonucleotrihelicate (II). The
attached nucleotides could further interact with their complementary base pairs to effect
anot:er degree of self-assembly.
Chelate effects have been applied to various novel multicenter metal complexes to
yield self-assembling inorganic double 17, triple18, and meso' 9 -helices, as well as doublestranded, non-helical metal complexes 20 . For example, double helices can be formed
Lehn, J.-M, Angew. Chem. 1988, 100, 92. Angew. Chem. Int. Ed. Engl. 1988, 27, 90; ibid. 1990, 102,
1347 and 1990, 29, 13-104. Koert, U.; Harding, M.M.; Lehn, J.-M., Nature 1990, 346, 339. Zarges, W.;
Hall, J.; Lehn, J.-M.; Marquis-Rigault, A., Proc. Natl. Acad. Sci. USA 1993, 90, 5394. Constable, E.C.,
Tetrahedron 1992, 48, 10013. Constable, E.C.; Edwards, A.J.; Raithby, P.R.; Walker, J.V., Angew. Chem.
1993, 105, 1486, Angew. Chem. Int. Ed. Engl. 1993, 32, 1465. Potts, K.T.; Keshavarz-K, M.; Tham, F.S.;
Abruna H.D.; Arana, C.; Inorg. Chem. 1993, 32, 4450. Airey, A.L.; Swiegers, G.F.; Willis, A.C.; Wild,
S.B.; J. Chem. Soc. Chem. Commun. 1995, 695.
18 Constable, E.C., Angew. Chem. 1991, 103, 1482; Angew. Chem. Int. Ed. Engl. 1991, 30, 1450. Williams,
A.F.; Piguet, C.; Bernardinelli, G., ibid. 1991, 103, 1530 and 1991, 30, 1490. Bernardinelli, G.; Piguet, C.;
Williams, A.F.; ibid. 1992, 104, 1626 and 1992, 31, 1622. Kramer, R.; Lehn, J.-M.; DeCian, A.; Fischer, J.,
ibid. 1993, 105, 764 and 1993, 32, 703. Potts, K.T.; Horwitz, C.P.; Fessak, A.; Keshavarz-K, M.; Nash,
K.E.; Toscano, P.J., J. Am. Chem. Soc. 1993, 115, 10444. Zurita, D.; Baret, P.; Pierre, J.-L., New J. Chem.
1994, 18, 1143. Piguet, C.; Hopfgartner, G.; Williams, A.F.; Bunzli, J.-C. G., J. Chem. Soc. Chem.
Commun. 1995, 491
19 Albrecht, M.; Kotila, S., Angew. Chem. Int. Ed. Engl. 1995, 34(19), 2134.
"o Ruttimann, S.; Piguet,C.; Bernardinelli, G.; Bocquet, B.; Williams, A.F., J. Am. Chem. Soc 1992, 114,
4230. Bilyk, A.; Harding, M.M.; Turner, P.; Hambley, T.W., J. Chem. Soc. Daton Trans. 1994, 2783.
17
1. Introduction
when a bis-bidendate ligand is allowed to react with a metal ion. For double helices,
suitable metal ions must favor four-coordinate geometry.2
Artificial oligonucleosides,
which have been shown to exhibit positive cooperativity, have been constructed via the
coordination of copper(I) ions with tetrathymidine tribipyridine ligands in a tetrahedral
arrangement (Figure 5).22 This example shows clearly how novel constructs based on
non-natural subunits can yield organizational frameworks which rival many found in
nature.
An elegant example which incorporates both a metal chelate and hydrogen
bonding in the self-assembly process is the well-known G-quartet (Figure 6).23 The alkali
metals have been shown to direct the association of four guanine residues into this
arrangement, in a manner which is dependent upon the metal used. The four guanine
residues, which contain the self-complementary Watson-Crick and Hoogsteen edges
associate to form a tetramer through the effects of hydrogen bonding, and upon nucleation
of the monovalent cation.
H
R
HN Y_"Nll.
Hoogste.n
face
ell
n
ce
RH''
..
N.
N-H
H
H-N,
_N•
R
.
N,
N""R
Figure 6. Self-Assembly of a G-quartet. Metal nucleation promotes guanine association.
Hydrogen bonding patterns dictate the overall square planar symmetric arrangement
Dietrich-Buchecker, C.O.; Sauvage, J.-P.; Kintzinger, J.-P.; Maltese, P.; Pascard, C.; Guilhem, J., New J.
Chem. 1992, 16, 931.
21 Dietrich-Buchecker, C.O.; Guilhem, J.; Pascard, C.; Sauvage, J.-P., Angew. Chem. Int. Ed. Engl. 1990,
29, 1154. Dietrich-Buchecker, C.O.; Sauvage, J.-P., ibid. 1989, 28, 189.
22 Koert, U.; Harding, M.M; Lehn, J.-M., Nature 1990, 346, 339. Pfeil, A.; Lehn, J.-M., J. Chem. Soc.,
Chem. Commun. 1992, 383.
23 Barr, R.G.; Pinnavaia, T.G., J. Phys. Chem. 1986, 90, 328-334. Williamson, J.R.; Raghuraman, M.K.;
Cech, T.R., Cell 1989, 59, 871-880.
1. Introduction
1.5 Hydrogen Bond-Directed Self-Assembly
Most of the synthetic work to date has focused on supramolecular structures
which assemble through hydrogen bonds.
The predictable directionality and overall
fidelity of the hydrogen bond makes it an effective interaction for directing selfassembly. 24 ,'2 5 Other weak and nondirectional interactions, such as Van der Waals and irtstacking attractions are difficult to use in designing molecular surfaces which are
complementary.
An understanding of the common patterns in hydrogen bonding is allowing the
synthesis of a variety of supramolecular structures. In the solid state, rules have been
delineated to allow the reasonable prediction of hydrogen-bonding packing patterns in
crystals. The design of molecular subunits that self-assemble into well-defined structures
in the solid state is an area of intense current interest. A recent discovery involves the
interaction between 2-amino-6-methylpyridine and carboxylic acids (Figure 7), 26 which
self-assemble into alternating cocrystal structures.
By changing the nature, size, and
orientation of the spacer groups, which link the hydrogen-bonding subunits, the packing
of the two components can be controlled.
Figure 7. The packing pattern between bis(acylaminopyridines) and dicarboxylic acids.
For discussions of hydrogen bonding in molecular crystals, see: Ref. 14, and: Lieserowitz, L.; Tuval, M.
Acta Crstallogr.1978, B34, 1230-1247. Lieserowitz, L.; Hagler, A.T. Proc.R. Soc. London A 1983, 388,
133-175. Yang, J.; Marendaz, J.-L.; Hamilton, A.D., Tetrahedron Lett. 1994, 35, 3665-3668. Zerkowski,
J.A.; MacDonald, J.C.; Whitesides, G.M., Chem. Mater. 1994, 6, 1250-1257.
25 Fersht, A. R. TIBS 1987, 12, 301.
26 Fan, K.; Vincent, C.; Geib, S.J.; Hamilton, A.D., Chem. Mater. 1994, 6, 1113-1117.
24
1. Introduction
In solution one of the major challenges regarding the design of supramolecular
architectures involves minimizing the occurrence of disordered aggregates. Assemblies
which possess high symmetry can only occur using very specific elements of molecular
recognition. Selecting out relatively small architectures, such as dimers and trimers,
requires a great deal of design prowess. The cyclic trimerization of one such design
(Figure 8) was clearly demonstrated using vapor pressure osmometric measurements as
27
well as proton NMR dilution studies.
I
Figure 8. Cyclic trimerization of pyrido[4,3-g]quinolinedione through hydrogen bonding.
Recently, much of the focus has been shifted to assemblies which occupy three
dimensions. 2 8 Such constructs have provided a wealth of thermodynamic information
regarding the interplay of entropic and enthalpic effects on the assembly process.
Techniques for characterizing noncovalently bound species in organic solution have been
carried out on the 1:1 complex between cyanuric acid and melamine (Figure 9).29
Zimmerman, S.C.; Duerr, B.F., J. Org. Chem. 1992, 57, 2215-2217.
28 Ducharme, Y.; Wuest, J.D., J. Org. Chem. 1988, 53, 5787-5789. Seto, C.T.; Whitesides, G.M., J. Am.
Chem. Soc. 1990, 112, 6409-6411. Seto, C.T.; Whitesides, G.M., J. Am. Chem. Soc. 1991, 113, 712-713.
29 Seto, C.T.; Mathias, J.P.; Whitesides, G.M., ibid. 1993 115, 1321-1329. Seto, C.T.; Whitesides, G.M.,
ibid. 1993, 115, 1330-1340. Mathias, J.P.; Seto, C.T.; Simanek, E.E.; Whitesides, G.M., ibid. 1994, 116,
27
1725-1736.
25
25
1. Introduction
1. Introduction
HI
H
I
N
melamine
N
YN
H NH.N
N..
N•
HN
H' N
0
N•.N
N
0.,~O
cyanuric acid
H
Figure 9. The complex of cyanuric acid and melamine through hydrogen bonds.
A series of hydrogen bound assemblies have been prepared using this complex in
order to gain further insights into the thermodynamics of the self-assembly process. In
one such study a (1+3) supramolecular complex (Figure 10) was formed by covalently
attaching three melamine units to a central 'hub' and then complexing the resulting
tris(melamine) to three cyanurates.30
Using 'spokes' which are conformationally
compatible, well-defined 1 : 3 complexes have been characterized using this design. The
covalent attachments provide a degree of 'preorganization' to the network and limit its
assembly to defined aggregates.
The importance of preorganization
has been
demonstrated in a variety of other studies. 31 A further adaptation of this system was
explored by connecting two cyanurates together to yield multilayered structures in a (2+3)
+
1+3
3
Figure 10. (1+3) Supramolecular complex consisting of a single tris(melamine) unit
and three cyanurates.
30
Seto, C.T.; Whitesides, G.M., J. Am. Chem. Soc. 1993, 115, 905-916.
1.Introduction
.
Introduction
1
arrangement. 32 Such studies have been carried out to determine the relationships between
molecular structure and geometry, as well as the stability of the resulting aggregates.
In further exploring the dynamics and applications of self-assembly, structures
which contain large, closed-shell cavities have recently been designed. One such design
33
uses cyclic peptides to form tubular assemblies on the nanometer scale.
These
structures (Figure 11) self-assemble intermolecularly through hydrogen bonds in a
manner analogous to that of helical peptides. Having specific internal diameters, such
systems display good channel-mediated ion-transport activity34and have recently been
used to study channel-mediated water organization and self-diffusion. 35 It has been
hypothesized that such structures could be designed for use as cytotoxic agents,
membrane transport vehicles, and drug-delivery systems.
0
No
0
0 HN L
L
0
n,0
NN
0
L
09 L
P"
0
0
ý0ý0
NN
C34,
L P4ý01
HN
0
0
Figure 11. The chemical structure and resulting tubular self-assembly of a cyclic peptide.
J., Jr., Angew. Chem., Int. Ed. Engl. 1990, 29, 245-255 and the references therein. Bryant, J.;
Ericson, J.; Cram, D.J., J. Am. Chem. Soc. 1990, 112, 1255-1256.
32 Seto, C.T.; Whitesides, G.M., J. Am. Chem. Soc. 1991, 113, 712-713.
33 Khazanovich, N.; Granja, J.R.; McRee, D.E.; Milligan, R.A.; Ghadiri, M.R., J.Am. Chem. Soc. 1994,
116, 6011-6012. Ghadiri, M.R.; Granja, J.R.; Milligan, R.A.; McRee, D.E.; Khazanovich, N., Nature 1993,
366, 324-327.
34 Ghadiri, M.R.; Granja, J.R.; Buehler, L.K., Nature 1994, 369, 301-304.
35 Engels, M.; Bashford, D.; Ghadiri, M.R., J. Am. Chem. Soc. 1995, 117, 9151-9158.
31 Rebek,
1. Introduction
1.6 Dimeric Self-Assembly Through Hydrogen Bonds
Recently, novel compounds have been constructed which self-assemble reversibly
into semi-spherical dimers through hydrogen bonding. In the first example of this design
(Figure 12), two glycoluril moieties were connected through a rigid durene 'spacer' to
form a self-complementary molecule with an inherent concavity. 36 This so-called 'tennis
ball' which features a hollow cavity of approximately 50-55 cubic angstroms has been
shown to reversibly encapsulate a variety of small molecules and noble gases in certain
non-competing solvents. 37 ,'38 By using various side chains on the glycoluril moiety,
increased solubility and acid-base control 38 of the assembly process have been observed.
11
HRH
.
R
N
2
R
N4
)
IR
N N
0-<N IN C0
RRH
(R = Ph, 4-MeN-Ph, CO,2Et)
Figure 12. Self-Assembly of self-complementary molecules into 'tennis ball'.
Based upon this general design, several new compounds have been synthesized
which aggregate into dimers of comparable and substantially larger size (Figure 13).
Although not possessing 'ideal' molecular recognition 39, molecules based upon the
Wyler, R.; de Mendoza, J.; Rebek, J., Jr. Angew. Chem. Int. Ed. Engl. 1993, 32, 1699-1701.
37 Branda, N.; Wyler, R.; Rebek, J., Jr. Science 1994, 263, 1267-1268.
38 Branda, N.; Grotzfeld, R. M.; Valdez, C.; Rebek, J., Jr. J. Am. Chem. Soc. 1995, 117, 85-88.
39Based upon molecular modeling simulations using MacroModel 3.5X (MM2 and AMBER force fields):
Mohamadi, F.; Richards, N.B.; Guida, W.C.; Liskamp, R.; Lipton, M.; Caufield, C.; Chang, G.;
Hendrickson, T.; Still, W.C., J. Comput. Chem. 1990, 11,440-467.
36
1. Introduction
naphthalene (II) and bridged anthracene (III) spacers self-assemble into dimers which
undergo interesting host-guest 4 chemistry with a variety of neutral guests. 41 This occurs
despite the presence of sizable 'holes' in their dimeric structures.
substantially larger tetraurea compounds, which incorporate
The newer and
a new mode of
42,43
43 One of
complementarity, have been shown to encapsulate a wide variety of guests.42
the many implications of such dimerization has been recently demonstrated using
molecule V (below), which can accerlerate certain Diels-Alder reactions through the
simultaneous encapsulation of both diene and dienophile. 43
HR
4
i
I
H 4
HRH
NjN
~R
HRH
0<
JNH
I
N N
HR
NN
Figure 13. Several Self-Complementary molecules having two-fold symmetry.
Another interesting molecule, which has three-fold symmetry, has been recently
studied which also dimerizes reversibly. The so-called 'jelly doughnut' (Figure 14) is
Cram, D. J.; Cram, J. M. Science 1974, 183, 803-809.
Valdes, C.; Spitz, U. P.; Kubik, S. W.; Rebek, J., Jr. Angew. Chem. Int. Ed. Engl. 1995, 34, 1885-1887.
Valdes, C.; Spitz, U. P.; Toledo, L. M.; Kubik, S. W.; Rebek, J., Jr. J. Am. Chem. Soc. 1995, 117,
12733-12745.
42 Meissner, R. S.; Rebek, J., Jr.; Mendoza, J. d. Science 1995, 270, 1485-1488.
43 J. Kang; J. Rebek, Jr. in press.
4
41
1. Introduction
based upon a hexamethyltriphenylene spacer, and has been shown to permit the passage
of guests into or out of its cavity at a relatively slow rate. 44
HRH
o= NIN >=0&
N
N
.~--
R
H
H'N
RH
N
NOR
XRR
R
O
NNR HNI H
H
Figure 14. The 'Jelly doughnut' which self-assembles into dimers of peculiar symmetry.
The common feature which is inherent to all of these molecules is the lack of
flexibility in both their spacers and glycoluril moieties.
This rigid character is
responsible not only for the predictable nature of the assembly process, but also for
certain profound observations regarding the thermodynamics of their host-guest
chemistry.
In order to determine the importance of such rigidity a project has been
undertaken to synthesize and study the effects of flexibility in the spacer region of similar
motifs.
44
Grotzfeld, R. M.; Branda, N.; Rebek, J., Jr. Science 1996, 271, 487-489.
2. Desi2n
2. Design
2.1 Flexibility
In designing the initial tennis balls (Figures 12-14), the groundbreaking
researchers had sought to construct molecules of definite conformation (that is, having a
very limited number of low-energy conformations) in order to maximize the probability
for self-assembly. In each case, in fact, at least one of the lowest energy conformations
matched the 'ideal' shape considered necessary to affect a suitable self-complementarity.
Although this ideal was certainly realized, the relative similarity of these molecules
possesses an inherent weakness with regard to understanding certain aspects of the
assembly process. For this reason it has been desirable to carry out such measurements
using a similar design (with glycoluril molecular recognition sites), and yet incorporating
a greater degree of flexibility and, indeed, uncertainty into the spacer region.
Despite various stochastic simulations, it was uncertain how increased flexibility
would affect the self-assembly and binding characteristics of such molecules. A previous
study on flexibility has shown clearly that monomers capable of undergoing free (3600)
rotation about single bonds are precluded from forming dimers. 43 This is because the
monomer itself is capable of forming at least two intramolecular hydrogen bonds via a
twisted conformation (Figure 15).
Such intramolecular hydrogen bonding apparently
0
NAN.H
NyNH
0
Intramolecular Hydrogen Bonding
Figure 15. Flexible 'softball' which was shown to collapse via intramolecular hydrogen bonds.
43
The unpublished results of Meissner, R.S. and Rebek, J., Jr.
2. Design
31
dictates the lowest energy conformation as one incapable of forming dimers. Although
this study showed that self-assembly did not occur under some conditions, it is unclear
whether a certain guest, or guests, might have been used to affect the desired assembly
via an initial nucleation event. Encapsulation studies using the rigid dimers have revealed
that the thermodynamic driving force for such nucleation is closely related to the
character of the aggregates themselves.
2.2 Thermodynamic Aspects of Flexibility
Extensive encapsulation studies using the various rigid molecules have shown that
the enthalpic driving force for encapsulation is most likely the Van der Waals interactions
between the inside walls of the aggregate capsules and the outside surface of the guests. 39
What is most profound regarding this phenomenon is that the observed selectivity for
these interactions is dependent upon the shape of the capsule itself. The nature of this
selectivity is then a manifestation of the rigidity itself. That is, if the capsule had the
ability to 'conform' to the shapes of its various guests, then it is unlikely that such
selectivity would be observed to the extent that it is.
Whereas the rigid aromatic spacers present in these molecules are incapable of
conforming over a wide range of similar guest molecules (or gases) upon nucleation, an
ideally designed molecule having a more flexible spacer might have this ability. Thus, it
is possible that flexible molecules based on this general motif could exhibit more 'general'
binding characteristics. Although the potential reduction in selectivity is not necessarily a
positive effect, it is certainly a possibility that should be explored in order to better
understand the dynamics of the assembly and inclusion events.
In order to study flexibility, a new approach to constructing molecules with
varying degrees of flexibility, and yet still utilizing a concave arrangement of the
glycoluril moieties, has recently been sought.
.
Design
2
2.3 Using Macrocycles to Explore Flexibility
In designing a new approach to constructing self-complementary molecules using
the glycoluril moiety, several important factors had to be considered.
First, only
molecules of similar size and molecular recognition are of interest in comparing their
thermodynamics to that of the formerly discussed 'rigids'. Second, it will be necessary to
incorporate the flexibility in a manner that prevents the intramolecular interactions which
have been observed previously (Figure 15). Finally, it would be most desirable to utilize
a modular approach, by which a variety of molecules could be constructed using different
sub-spacer elements.
Such an approach would provide a means to vary the overall
geometry and flexibility of these molecules, as well as, to incorporate different
functionalities in the spacer region.
To satisfy these considerations two closely-related modular approaches have been
envisioned for the construction of a variety of self-assembling macrocycles (Figure 16).
In the first case the cx,a-diolic fragment VI is used as a common module for the
construction of a series of tetraester macrocycles. Using a similar approach, the x,a-diamino fragment VII is used to construct both tetraamide and tetraimino macrocycles.
f
m
0
NH
N
N•
R
N
N-H
0
(X=O)J
HO
(X= NH)
OH
0=<
N
N
PR'p
VI
H2 N
NH 2
0<N
N>o
N N
ý R
VII
Figure 16. Modular approaches to self-complementary macrocycles based on esters, amides and imines
2. Design
The length, flexibility and general 'character' of the sub-spacers can be varied to obtain
macrocycles, which vary widely in their overall sizes, geometries and host-guest
interactions 41' 44
Molecular modeling has revealed several viable choices among the many
tetraester compounds that could be considered (Figure 17). Among these, those which
contain the oxalic, malonic, maleic and isophthalic moieties most closely resemble the
molecular recognition patterns present in the durene-based and bridged-anthracene-based
dimers. The hydrogen bonding pattern of the tetraester ball which contains the oxalic
spacer closely resembles that of the original tennis ball (durene spacer). Whereas the
corresponding pattern that occurs using the isophthalic spacer closely resembles that of
the bridge-anthracene (IH) - with the glycoluril hydrogens directed somewhat inward.39
The maleic and malonic cases, then, closely resemble patterns which occur somewhere
between these two extremes. The best molecular recognition appears to occur when the
oxalic and malonic sub-spacers are used.
H
R
H
NN
N
N
o
0 N)
O0
(X=CH, N)
Figure 17. The optimal sub-spacers for tetraester macrocycles based on molecular modeling.
Similar geometries
were
calculated
with the corresponding
tetraamide
macrocycles. However, with the free amide N-H's present, it has been found that shorter
spacers (oxalic and malonic) are most feasible due to the presence of intramolecular
44
Cram, D. J.; Cram, J. M. Acc. Chem. Res. 1978, 8-14.
2. Design
hydrogen bonding. This hydrogen bonding (Figure 18) tends to impart a bending or
twisting conformation to the macrocycle, thus directing the molecular recognition
surfaces in directions which are unsuited to optimal assembly. However, the dynamic
nature of such molecules, at normal temperatures, would certainly not preclude selfassembly of these molecules. Another alternative is to substitute the amides with small
groups such as methyl groups.
Figure 18. Intramolecular hydrogen bonding responsible for bending and/or twisting in tetraamides.
Among several sub-spacers which could be used in forming tetraimines, the
malonaldehyde-based macrocycle (Figure 19) appears to be an excellent choice. Its
monomer contains a significant amount of rigidity (much more than the corresponding
tetraester and tetraamide macrocycles) and prefers conformations which appear to be
ideal for dimeric self-assembly. Similar macrocycles (aside from the glycolurils) have
45
been produced in reasonable yield using various metal templates, including Cun.
14
2N
H RH
NH2
N.
NNtN
O-
N
,N
HR
NO
Cu(OAc) 2
'H
+
HRH
SH
H/
(O
O
H
N
N
N
N
H
'H
H
R
O=NiN
0
HRH
Figure 19. The malonaldehyde-based tetraimine macrocycle. Constructed using metal templates, such a
macrocycle is expected to readily undergo dimeric self-assembly.
Nelson, S.M.; Esho, F.S.; Drew, M.G.B.J. Chem. Soc., Dalton Trans. 1982, 407. Drew, M.G.B.;
Nelson, J.; Esho, F.S.; McKee, V.; Nelson, S.M. J. Chem. Soc, Dalton Trans. 1982, 1837.
45
2. Design
2.4 Implications of Metallic Host-Guest Interactions
In utilizing heteromacrocycles, there exists the option of exploiting secondary
host-guest interactions in the form of metal binding to enhance their synthesis, geometry,
and to a certain extent, rigidity. The use of template synthesis to affect the construction
of macrocycles is well known in contemporary chemistry.4 6
As previously explained
such a technique could be utilized to produce the desirable tetraimine macrocycle.
However, template effects are also prevalent in the chemistry of crown ethers47, as well
as, macrocyclic esters and amides. 48
Although the binding abilities of crown esters, relative to their ether counterparts,
is somewhat diminished, certain macrocycles have been shown to emulate crown ethers
quite closely.4 9 These interactions have been used to generate macrocycles containing the
2,6-dicarboxylpyridine subunit in surprisingly high yields.o This phenomenon could be
exploited to generate tetraester macrocycles, which possess metal-binding properties
rivaling those of the 18-crown ethers, in high yield (Figure 20).
1
+
Figure 20. A tetraester macrocycle which is expected to readily complex certain metals.
Hoss, R.; V0gtle, F. Angew. Chem. Int. Ed. Engl. 1994, 33, 375-384.
Pedersen, D. J. J. Am. Chem. Soc. 1967, 89, 7017-7036.
Hancock, R. D. Journalof Inclusion
Phenomenaand MolecularRecognition in Chemistry 1994, 17, 63-80.
46
47
48van Veggel, F. C. J. M.; Verboom, V.; Reinhoudt, D. N. Chem. Rev. 1994, 94, 279-299.
Alexander, V.
Chem. Rev. 1995, 95, 273-342. Izatt, R. M.; Pawlak, K.; Bradshaw, J. S. Chem. Rev. 1995, 95, 25292586.
49 Izatt, R. M.; Lamb, J. D.; Asay, R. E.; Maas, G. E.; Bradshaw, J. S.; Christensen,
J. J.; Moore, S. S. J.
Am. Chem. Soc. 1977, 99, 6134-6136.
50 Bradshaw, J. S.; Asay, R. E.; Maas, G. E.; Izatt, R. M.; Christensen, J. J.
J. Heterocyclic Chem. 1978,
15, 825.
3. Synthesis
3. Synthesis
This chapter outlines the efforts made towards the synthesis of the modular
fragments described in Chapter 2, as well as, aspects pertaining to the formation of the
target macrocycles. The additional section (section 3.6) involves an attempt to synthesize
a new glycoluril-diene compound.
3.1 Fragment Construction - Initial Glycoluril
In choosing an adequate glycoluril to serve as the general molecular recognition
structure for these studies, the feasibility of several previously utilized examples was first
considered. These were the bis(phenyl)- 36,37 , p,p'-bis(alkylaryl)- 43 and the bis(alkylester)glycolurils 38' 39' 4 2 . Three primary considerations influenced the decision not to use any of
these types of glycolurils.
First, solubility is a very important factor in designing
molecules which will be studied in a variety of solvents. The bis(phenyl)glycoluril has
demonstrated poor solubility in most organic solvents - due, presumably, to aromatic
stacking interactions. This molecule was used with the early 'rigid' molecules because of
51
its ready availability in high yield (-85%) via the condensation of benzil and urea.
Another important factor is the availability of the glycoluril in question.
The p,p-
bis(heptylaryl)glycoluril variant, which was utilized to impart outstanding solubility
characteristics to the rigid molecule V, was obtained from the corresponding benzil,
which was quite difficult (and expensive) to produce.
Aside from solubility and
availability, stability is also a very important consideration for this particular project. The
stability of the glycoluril esters has been problematic in previous studies. Because this
project will involve a great deal of synthesis, the use of ester glycolurils was, thus,
avoided.
51
Bulter, A.R.; Leitch, E., J. Chem. Soc., Perkin Trans. 111980, 103
3. Synthesis
Because a relatively large quantity of a glycoluril with excellent solubility
characteristics would be necessary to produce the target macrocycles, the p,p'-bis(hexyloxyphenyl)glycoluril 4 was first chosen. The compound was synthesized in four steps on
a large scale and in high-yields from relatively inexpensive starting materials (Scheme 1).
The synthesis involves the initial oxidation of anisoin using CunSO 4 '5H20 to produce the
intermediate benzil, 52 which was then deprotected using pyridinium hydrochloride to
yield the phenolicbenzil 2. 53 These two steps are carried out on a very large scale, in
nearly quantitative yields, with a minimal purification in each case. Compound 2 can
then be substituted, using typical conditions, with a variety of alkyl chains to ultimately
yield glycolurils of varying solubility. The hexyl side chain was chosen based upon
success of the previously mentioned p,p-bis(heptylphenyl)glycoluril. Adequate yields of
4 were then obtained via the condensation reaction of benzil 3 with urea in the presence
of acid.
Scheme 1. General Alkyloxyaryl Glycoluril Synthesis
0
OH
0
0
Cu(")S04.5H2 0
Pyridine
OMe
MeO
"2H-
MeO
OMe
1
(93%)
0
0
0
0
Pyridine.HCI
A
MeO
OMe
0
(97%)
>
HO
0
OH
0
0
t-BuOK
HO'O
OH
Hexyl Bromide
DMF, A
(86%)
C6H,o30
OC6 H,3
3
) IUrea
0
C6 H130'
0
OC6H13
HR
0
TFA
Benzene, A
(72%)
53
N
N
N
H
4
52
N
Gilman, H.; Broadbent, H.S. J. Am. Chem. Soc. 1948, 70, 2619-2621.
Somin, I.N.; Kuznetsov, S.B. Chem. Abstr. 1960, 10950i.
R4
0
H
o-%H)
3. Synthesis
3.2 Fragment construction - otx-Diolic Fragment
Glycoluril 4 was substituted with 1,4-dichloro-2-butene in the presence of
potassium tert-butoxide and pyridine in a mixture of DMSO and THF (Scheme 2).
Yields of 30 to 48% were obtained depending upon the scale of the reaction. In order to
prevent the formation of the symmetric bis(olefin) side-product, an excess of the
glycoluril (8 to 1) was used. Although earlier syntheses had utilized ratios as high as 15
to 1 to obtain similar yields, no improvement was observed with 4 using such ratios.
Compound 5 was then available for protection and further elaboration.
Several protecting groups were explored to determine their feasibility in
protecting the olefin fragment 5.
Among these, only the tert-butyl carbamate (N-
BOC) 54and p-methoxylbenzyl (PMB) 55 groups have been used effectively to block the
glycoluril
Other groups
amides.
including
the benzyl
(N-Bn) 56
and (tert-
57
butyldimethylsilyloxy)methyl group 7can be introduced onto the fragment, but either
Fragment 5 was
decompose during later reactions or cannot be effectively removed.
protected using di-t-butyl dicarbonate 54 with dimethylaminopyridine 58 in THF in
reasonable yield (below).
Scheme 2. Synthesis of Boc-Protected Olefin Fragment
H R
NIN
o______0
N
R H
R=(
. OC6H,,)
t-BuOK
1=o
_/=-,
Pyridine
DMSO -THF
(30-48%)
o=N
<N
N
H
N
N
R H
5
('
2O
RBoc
o
__
_N
DMAP
THF
(83%)
N
o=0
o
NN
Bo'
R
Boc
6
Tarbell, D. S.; Yamamoto, Y.; Pope, B. M. Proc.Nat. Acad Sci. USA 1972, 69, 730-732.
Yoshimura, J.; Yamaura, M.; Suzuki, T.; Hashimoto, H. Chemistry Letters 1983, 1001-1002.
Note. PMB cannot be used to protect 5 itself due to the alkyloxylaryl moiety.
56 Velluz, L.; Amiard, G.; Heymbs, R. Bull. Soc. Chim. Fr. 1954, 1012. Green, T.W. Protective Groups in
Organic Synthesis; Wiley: New York, 1980, pp. 272-273, 332-334. Wuts, P.G.M.; Greeene, T.W.
Protective Groups in OrganicSynthesis; Wiley: New York, 1991; Vol. II, pp. 335-338.
57Benneche, T.; Gundersen, L.-L.; Undheim, K. Acta Chemica Scandinavica1988, 42, 384-389.
58 H$fle, G.; Steglich, W.; Vorbroggen, H. Angew. Chem. Int. Ed Engl. 1978, 17, 569-583.
54
55
3. Synthesis
The olefin 6 was then oxidized using N-methylmorpholine-N-oxide (NMO) with
catalytic osmium tetroxide in acetone/water (Scheme 3).59 Although a variety of methods
exist for the dihydroxylation of olefins using both KMnO 460 and OsO461, this method
appears to affect the highest consistent yields.
The reaction produces a mixture of
separable isomers in a ratio which varied between 3 to 1 and 5 to 1. Initially, it was
expected that the dominant isomer would be the desired cc,a-diol, 8. However, it was
later determined that the dominant isomer was in fact the less desirable P,P-diol, 7.
Scheme 3. The cis-Dihydroxylation of the Olefin Fragment using Osmium Tetroxide
R
IN IN
N
N
R BocB
Boc
HO
OH
HO
OH
Os0 4
NMO
sO
Acetone - H20
BcNIN
R=R.T.
6
NI
Boc
Boc R
R Boc
Boc
(62%)
7
(-4:1)
8
Although it was previously postulated that isomer 8 would be the major isomer of the
dihydroxylation reaction (the bottom face appears less hindered), this was not the case. The identity
of the major isomer was established by comparing its measured 1H NMR spectrum to that expected
for the two isomers. Specifically, its spin-spin coupling data were consistent with those anticipated
for 7, based on the analysis shown in Figure 21 (next page). This analysis predicts the weighted Jvalues for each isomer based upon their preferred conformations, which were ascertained using
modeling techniques 62 and the vicinal Karplus correlation. 63 The measured value for J1-2 of 8 Hz
(for the main product obtained via Scheme 3) is in close agreement with that predicted for the
bottom isomer (compound 7, 9 Hz). Whereas the measured value for J1-2 of 3 Hz for the minor
Schneider, W.P.; McIntosh, A.V. U.S. Patent 2 769 824. Van Rheenan, V.; Kelly, R.C.; Cha, D.Y.
Tetrahedron Lett. 1976, 1973. Corey, E. J.; Danheiser, R. L.; Chandrasekaran, S.; Siret, P.; Keck, G. E.;
59
Gras, J.-L. J. Am. Chem. Soc. 1978, 100, 8031-8034.
60Fatiadi, A. J. Synthesis 1987, 85-127.
61 Schroder, M. Chem. Rev. 1980, 80, 187-213.
62 Molecular Modeling was performed using Macromodel 3.5X (MM2 force field).
63 Karplus, M. J. Am. Chem. Soc. 1963, 85, 2870-2871.
40
3. Synthesis
product (see Scheme 3) is in close agreement with that predicted for the top isomer (compound 8,
2.5Hz).
A-7980a--..40.,5
2 Q.
A-7
.=-0Hz
j 12
2
2.=
.ý05
-5Hz
H
.(OH)HC
+
R2 N "
HO
CIH(OH)NR2
HO
@
Q=163F
J
J'-2,0 .= -9.5Hz
-(OH)
,
H
-H3
1529
.=-8.5Hz
HO H2
H2
OH
+
CH(OH)H HI
R2N
Hi
NR2
Figure 21. Vicinal coupling analysis of the two isomers obtained from Scheme 3. The top analysis is
for the hypothetical cx,ac-diol (8), and the bottom analysis is for the corresponding P,3-diol (7).
Another method for producing the desired isomer (Scheme 4) was examined
based upon the observation that applying the dihydroxylation procedure to the
unprotected fragment 5 often resulted in a much lower ratio.
In fact, at elevated
temperatures an optimal ratio as low as - 2 to 1 was measured. The two isomers, still as
a mixture, were then BOC-protected to produce the tetra-protected (carbamate/carbonate)
9, and its corresponding isomer.
These isomers were finally reacted with K2CO 3 in
excess methanol to affect the selective removal of the carbonate groups. 64
After
separation the desired cx,ca-diol was then obtained in overall yields as high as 30%.
Although this methodology appeared to significantly compensate for the poor selectivity
observed in the dihydroxylation reaction, it has proven to be difficult to reproduce
reliably due to the inconsistency of the final hydrolysis.
64
Olofson, R. A.; Schnur, R. C. Letrahedron Lett. 1977, 18, 1571-1574.
3. Synthesis
Scheme 4. An Alternate Route to the Desired Diol
HO
N
OsO4
N
NMO
IN
Nj-N
R
HRH
R=
R=-.~OceH13
0"
Acetone/O
OH
HO
BOC2O
'=\/NT=<
N
HO
-2C0
MeO
NIN
R BOC
THF
R
HHBO(
Isomer Ratio -2:1
O
OBOC
BOCO
0
NIINý=
R
H
OH
9
A
0
OH
N
0
NIN
BO6 R BOC
(Atps3
(3 Steps -30% )
8
5
In an attempt to avoid the selectivity problems encountered with the osmylation reactions,
the alternative 'wet' PrMvost reaction6 5 was performed on the olefin 6.66 Instead of producing the
desired isomer, a vigorous acidic hydrolysis of the intermediate dioxolenium salt (Scheme 5)
produced the P,3-diacylester compound 10. Because hydrolysis of the intermediate salt should
yield an asymmetric mono-acetate, it can be speculated that 10 is a either the result of multiple
nucleophilic substitutions (in an essential equilibration to this less-hindered species), or the result of
a successful reaction producing the 'wrong' isomer, followed by tranesterification. In any case, the
wrong isomer was once again produced. Various attempts to 'gently' hydrolyze the dioxolenium
intermediate, while still preserving the necessary BOC-protection, failed.
Scheme 5. Failed Woodward-PrFvost Reaction
AcO
0NRN N
0 <
NR
Boc
R=(-
O
B
Boc
1) 12AgOAc, HOAc
2) H20, HOAc, A
OAc
NNR
=o
=
N"N
RH
OCSHI)
10
Although
other
methods
exist
for
carrying
out
the
Woodward-PrMvost
67
transformation, these utilize different reagents to produce the common dioxolenium intermediate.
65Prdvost, C. Compt. rend. 1933, 196, 1129. ibid. 1933, 197, 1661.
Woodward, R. B.; Brutcher, F.V., Jr. J.Am. Chem. Soc. 1958, 80, 209-211. Bunton, C. A.; Carr, M. D.
JCS 1963, 770-775. Ellington, P. S.; Hey, D. G.; Meakins, G. D. J. Chem. Soc. (C) 1966, 1327-1331.
67 Cambie, R. C.; Rutledge, P. S. Organic Synthesis 1979, 59, 169-175.
Mangoni, L.; Adinolfi, M.;
Barone, G.; Parrilli, M. LetrahedronLett. 1973, 45, 4485-4486. Horiuchi, C. A.; Satoh, J. Y. Chemistry
Letters 1988, 1209-1210.
Campi, E. M.; Deacon, G. B.; Edwards, G. L.; Fitzroy, M. D.; Giunta, N.;
Jackson, W. R.; Trainor, R. JC.S. Chem. Comm. 1989, 407-408.
66
3. Synthesis
Thus, the same results would occur if these methods had been attempted. Instead, this procedure
was further investigated using an entirely new building block which incorporates PMB protection
(see Section 3.4). While this building block was under construction, preliminary cyclization studies
were undertaken using primarily the P,[-diolic fragment 7, in order to determine the feasibility of
certain methodologies.
3.3 Exploring Tetraester Cyclization Methods
Using primarily the
4,~-diolic fragment 7, preliminary cyclization studies were undertaken
to determine the feasibility of various methodologies in the construction of the target tetraester
macrocycles. The synthesis of crown-type macrocycles, such as that depicted in Figure 20, has
been carried out using a variety of traditional methods. 68 However, one method which exploits the
ability of tin to promote a 'covalent-template' in certain reactions, appeared perfectly suited to
construct such tetraesters. This method involves the formation of cyclic stannoxanes from vicinal
diols. 6 9 Such stannoxanes, which tend to associate into dimers of definite geometry, can then be
reacted with diacid chlorides or anhydrides to form tetraester macrocycles in good yields. 70 This
methodology was applied to both the ca,c(x-diolic fragment 8 and its non-protected partner 11
without success under various conditions (Scheme 6 -next page).
The problem appears to involve the formation of the stannoxane itself as indicated by the
appearance of its 1H NMR spectra. Instead of producing the expected stannoxane of defined
spectra characteristics, the condensation reaction produced a mixture having a complex and
broadened' spectra - perhaps indicative of a polymeric mixture. Although no specific evidence
exists to prove or disprove this idea, it is theorized that the lack of rotational freedom within the
Bradshaw, J. S.; Maas, G. E.; Izatt, R. M.; Christensen, J. J. Chem. Rev. 1979, 79, 37-52. Weber, E.;
Toner, J.L.; Goldberg, I.; VOgtle, F.; Laidler, D.A.; Stoddart, J.F.; Bartsch, R.A.; Liotta, C.L. Crown Ethers
and Analogs, 1989, John Wiley & Sons. Cooper, S.R. Crown Compounds, Toward FutureApplications.
1992, VCH Publishers, Inc.
69 Considine, W. J. Journalof OrganometallicChemistry 1966, 5, 263-266.
70
Shanzer, A.; Mayer-Shochet, N.; Frolow, F.; Rabinovich, D. J. Org. Chem 1981, 46, 4662-4665.
Shanzer, A.; Libman, J.; Gottlieb, H.; Frolow, F. J. Am. Chem. Soc. 1982, 104, 4220-4225.
68
3. Synthesis
diolic fragment somehow precludes the formation of the stannoxane. Generally, the literature
methods involved the use of very simple glycols.
Scheme 6. Attempts to Produce Tetraester Macrocycles using Stannoxanes
oRB
N
ON
Bu,Sn Bu
OH
HO
Bu 2Sn(OMe) 2
Benzene, A
N
No
N
R
R=(
+
L
BoR
OH
Bu
O*
NJ.N
-0
R4
RN
oC6H1)
11
A
No
No Macrocycles
'Boc.
,Sn1
Bu
*O
IBu2Sn(OMe)2
0=
R=(
COCI
12
8
HO
N
0
0
ýBoc
o cH,)
CIOC
NIC
4A Sieves
NTN
BoI
-
ClOC
R
Benzene,A
4A Sieves
N
COCl
A
CHC1
No Macrocycles
<NN)_
NN N
L
+
0
j
13
At this point it was decided to attempt to produce the target macrocycles using a two-step
approach. Using this strategy the sub-spacer diacids are connected to the diolic fragments in a
stepwise manner, via the use of their corresponding benzylester-protected acid chlorides (Schemes
7-10). A general method was first sought to produce the mono-benzylester protected acyl chlorides.
The initial approach was to react the corresponding diacid chlorides with one equivalent of benzyl
alcohol and then separate the mono-protected product Although this method worked, the difficulty
in purifying the resultant mixtures resulted in relatively low yields of the acyl chloride. A more
successful scheme involved converting the highly-insoluble diacids into the corresponding monobenzylester protected acid (Scheme 7), which could be further activated in a straightforward
method using oxalyl chloride7 ' (Scheme 8).
The benzylation reaction involves using
tetrabutylammonium fluoride (TBAF) to both solubilize and 'activate' the carboxyl groups for
71
Szmuszkovicz, J. J. Org. Chem. 1964, 29, 843.
3. Synthesis
nucleophilic substitution with benzyl bromide. Consistent yields in the mid-20's have been
obtained by applying these conditions to a variety of diacid chlorides.
Scheme 7. mono-Benzylation of Diacids using TetrabutylammoniumFluoride
HO2 C l
COH
TBAF
BnBr
THF
(26%)
HO2C
C02Bn
14
Upon coupling the acid chlorides to the diolic fragment, the benzyl esters were cleaved via
catalytic hydrogenolysis 72 (below). With sufficient quantities of the diacid fragment 16, several
attempts were made to activate the acids and affect the cyclization with another equivalent of the
diol. These attempts failed due to problems encountered with the various activation steps.
Scheme 8. Synthesis of B,B-Diacidic Franment
0
HO2 C
I Nk
CO 2 Bn
(COCI)2
DMFcat
CIOC
,
CO 2 Bn
DCE
BoON
7
TEA
DCE
R ++
OBn
0
0
(85%)
14
0y...). OBn
NN 0o
0
;
0
15
O
0
Boc-NN
Boc
N
0
B
0
0
0j
O
0
H2
OBn
N
N
OBn
10% Pd/C
EtOH
Boc- N
ly
OH
NR
O
0
N
0
OH
R )R
Boc- N
(91%)
"0
0
0
16
In attempting to produce the desired macrocyclic isomers from fragment 16, three general
methods of activation were used. First, various methods were used to activate the diacid to its
corresponding diacid chloride, which was then reacted as a crude mixture, under high-dilution, with
the diolic fragment 7 in an attempt to affect esterification into the target tetraester macrocycles.
72
Heathcock, C.H.; Ratcliffe, R. J.Am. Chem. Soc. 1971, 93, 1746.
45
3. Synthesis
71
Unfortunately no macrocycles were produced via this general approach using oxalyl chloride,
PPh3CC4 73, and 1-chloro-N,N,2-trimethylpropenylamine 74as activating agents (Scheme 9). The
general nature of these failures appears to reside in the activation step itself, which is why these
different reagents were tested. It is possible that, upon formation of the first acid chloride, the
remaining acid reacts with it and forms an intermediate anhydride. The anhydride then reacts with
the diolic fragment to form linear polymers which have proven difficult to separate and classify.
Scheme 9. Cyclization Attempts using Acvl Halide Activation
OCIb
C(
t
7
NEt 3
(High-Dilution)
I
Macrocycle Isomers
CH2C12
The second method employed utilized a mixed-anhydride strategy to activate the diacid.
Upon formation of the mixed anhydride, the diol would then be added under high-dilution in the
presence of DMAP to induce esterification and cyclization (Scheme 10). An ideal system for this
strategy uses carboxylic 2,4,6,-trichlorobenzoic anhydrides, which have been successfully applied
to the synthesis of many large-ring lactones. 75 As with the acid chloride attempts, this approach
failed to produce the desired macrocyclic isomers. Again, it is believed that an intramolecular
anhydride is produced upon activation with 2,4,5-trichlorobenzoyl chloride, thus leading to linear
polymers as before.
Lee, J. B. J. Am. Chem. Soc. 1966, 88, 3440-3441. Ramaiah, M. J. Org. Chem 1985, 50, 4991-4993.
Devos, A.; Remion, J.; Frisque-Hesbain, A.-M.; Colens, A.; Ghosez, L. J.C.S. Chem. Comm. 1979,
1180-1181. Haveaux, B.; Dekoker, A.; Rens, M.; Sidani, A. R.; Toye, J.; Ghosez, L. OrganicSyntheses,
1979, Vol. 59, 26-34.
75 Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull Chem. Soc. Jpn. 1979, 52, 19891993.
73
74
3. Synthesis
Scheme 10. Cyclization Attempts using Mixed-Anhydride Activation
H
o
coc•
7
-m
Macrocycle Isomers
DMAP
Toluene, A
(High-Dilution)
NEt3
THF
The final method used to produce the macrocycles from fragment 16 involved reacting the
diacid and diolic fragments together directly, under high-dilution, and in the presence of coupling
reagents.
Two reactions were studied using the coupling reagents dicyclohexylcarbo-diimide
(DCC)76 and 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDC) 77 .
As
before, these attempts failed to isolate any target macrocycles. Again, the possibility of intermediate
anhydrides cannot be ruled out as the cause.
At this point it was determined that the best strategy for producing the target macrocycles,
in this manner, is to actually induce the formation of the intermediate anhydride, isolate and
characterize it, and then react it under controlled conditions with the diol to produce the linear
Schenme 11. A New Approach to Macrocycles via a Symmetric Anhydride
o
%I
PMB
" N-
o0..
0
K
;I
"+
PMB.N 19,NN
OH
0
0
OH
PMIN YN _
R
R.
NRPMB
EDCI
DMAP
CH2CI2
(High-Dilution)
Diol
40
0
(plus isomer)
17
o
BN
"""r"
-".
P_+N
NX:
oN o
"PMB
Ho
HO
Acid Catalyst
o
Ca
Product Macrocyles
Benzene, A
(-H20)
Hassner, A.; Alexanian, V. LetrahedronLett. 1978, 46, 4475-4478.
77Dhaon, M. K.; Olsen, R. K.; Ramasamy, K. J. Org. Chem 1982, 47, 1962-1965.
76
3. Synthesis
products. These linear isomers can then be cyclized under high-dilution conditions to produce the
target of interest (Scheme 11). In order to allow the use of acid catalysis during the final
esterification, a new building block had to be obtained which did not incorporate the acid-sensitive
BOC protecting groups (see chapter 4). This new approach has not been applied to such a building
block at the writing of this manuscript
Another approach has been considered for the synthesis of a similar diester/diether
macrocycle in a straightforward manner. It was postulated that a diester fragment similar to
fragment 16, but using a haloacetyl halide instead of the benzylester-protected halide, could be
produced and directly substituted with the diol to produce the macrocycle 21 (Scheme 12). Only
minor modificatiolns were necessary to produce the diester compound 20 in good yield. As
expected cyclic o-ether ester compound (not shown) was a significant byproduct via a proximity
effect.
Scheme 12. Synthesis of Diester/Diether Macrocycle
HO
O
OH
Br
BO
Br
2,6-Lubdine
N
NoDMAP
I R
7
TBoc
0
Si
J
Bo N
2Li o
B2Li+
Bo
(80%/o)
Bc
N N,
N-
0
R
NN
Toluene
BOCN
o
N
oNU
N
B0 o
THF
R
Boc N
oOC
0 0 0N
.
. Boc
0
(plus isomer)
BoC R Boc
20
N
21
The attempt to close the macrocycle using the deprotonated diol fragment 7 failed due to an
unexpected decomposition of the anion itself.
Deprotonation of both 7 and 8 results in
deprotection and an apparent breakdown of the seven-membered ring moiety (Figure 22). In a
typical f-elimination, the alkoxide presumably eliminates the amide anion, thus forming an
intermediate epoxide. It is possible that the amide anion is stabilized by the BOC group. The
epoxide can undergo a variety of additions with either the amide ions or other alkoxides to form
complex mixtures. Such 'polymers' result whenever these diols are deprotonated using strong
bases, such as LDA. Another option for enhancing the nucleophilicity of the diols under neutral
3. Synthesis
conditions is to use a NP" catalyst78 However, this possibility has not been explored at the writing
of this manuscript
HO
I)HO
R )\R
NRNQ
N
Boc
N
'Boc
.0
N±N
N
I
N
Boc R Boc J
Figure 22. Decomposition of deprotonate diol via -e6limination.
Further investigations, in terms of cyclization methodology, involved aspects of
asymmetric sub-spacer introduction via a mono-protection scheme (as in Figure 23). Asymmetric
macrocycles, such as 22, could potentially be synthesized using a selective protection/deprotection
of the one of the diolic fragment's alcohols. Thus, a suitable protecting group was sought which
could be used to perform this function. Additionally, it would be preferable for such a blocking
group to be introduced selectively (without the excessive formation of the bis-protected fragment).
Whereas haloacetyl esters had already been shown to form their cyclic adducts when individually
present on the fragment, both the silicon-based protecting groups and the common benzyl ether79
group seemed ideal protecting groups in this context
HO
OP
NR
N N
0< RIN)=
.P RP'
Figure 23. Asymmetric Cyclization Strategy.
78
79
Yamashita, M. Synthesis, 1977, 803.
Czernecki, C.; Georgoulis, C.; Provelenghiou, C. TetrahedronLett. 1976, 3535.
H. Chem. Pharm.Bull. 1967, 15, 1803.
Iwashige, T.; Saeki,
3. Synthesis
It was already understood that, in order to substitute the fragment alcohols, some method
other than deprotection using a strong base would be necessary. Attempting to introduce the benzyl
ether blocking group was, thus, very challenging.
So challenging, in fact, that it was not
successfully introduced in adequate scale. The so-called Kuhn alkylation 80provided the only set of
conditions which produced characterizable benzyl ether products. This involved reacting the diol
with silver(II) oxide and benzyl bromide in DMF. Due to the difficulties optimizing these
conditions, the focus was shifted to silicon-based groups.
The first silicon group explored was terit-butyldimethylsilyl (TBDMS)."
This has been
82
used in previous studies to carry out such mono-protections based upon its steric hindrance. As
with other silicon-based protecting groups, TBDMS can be cleaved under neutral conditions using
TBAF.83 It was, indeed, introduced selectively with yields as high as 85%. However, the monoblocked fragment 23 was too hindered to carry out further elaborations (Scheme 13). Attempts to
couple two fragments in this manner using oxalyl - and malonyl dichlorides failed as well.
Scheme 13. Mono-Protection Using the TBDMS Group
OH
HO
OTBDMS
HO
N±N
O =
Bo
N
TBDMSCI
N
R Boc
R=(
-ý
O
DMAP
DBU
Toluene
R= oc#")(85%)
7
c1oC
N
0
0
N
+
N COCI
-
NEt 3
Toluene A .
No Reaction
N
Boc
Boc
23
It was then decided to explore the reactivity of the common trimethylsilyl (TMS) group in
this context. Although the yields of the corresponding mono-TMS protected fragment 24 were
significantly lower (63%), this friagment reacted with diacid chlorides such as oxalyl chloride, albeit
in low yields (Scheme 14). The bis-protected fragment 25 was then treated with TBAF in the
80
81
82
83
Ferguson, A. C.; Haines, A. H. J. Chem. Soc. (C) 1969, 2372-2375.
Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190-6191.
Hakimelahi, G.H.; Proba, Z.A.; Ogilvie, K.K. TetrahedronLett. 1981, 22, 5243.
Corey, E. J.; Snider, B. B. J. Am. Chem. Soc. 1972, 94, 2549-2550.
Synthesis
3
.
presence of oxalyl chloride in an attempt to induce cyclization. However, only a trace amount of
the compound 26 was isolated.
Schenme 14. Mono-Protection, Fragment Coupling, and Deprotection Using the TMS Group
0
HO
OH
HO
OTMS
TMSCI
N
N
N
o4>o
R=(oc
0
R
Boa
N N
Boo R Boc
O
N 0o-,•.••
Boc
0
NEt 3
Toluene
(31% - both diast.)
R NTMSO
N
S0
0TM
N
Boo- N
0
OTMS
o
(plus isomer)
0
0
TBAF
(0001)2
B oc -N
-.oc
B
Boc
NNR
, Boc
" N"•
o0 NN
R
N
(COCI)2
Do
DMAP
DBU
Toluene
(63%)
N
Bo" R Boc
Boc
)-NR
NEt 3
Tolene
Boc N
N
OjO
Boo-N
N
0
R+
0
0
Although the expected macrocycle was not isolated from the above reactions, this attempt
was carried out on a very small scale and is not necessarily indicative of this methodology's
potential. It is expected that, given sufficient quantities of the coupled fragments (e.g. 25), this
methodology can be used successfully to produce symmetric and asymmetric tetraester
macrocycles. In order to obtain these compounds on a larger scale, further studies were directed
towards the synthesis of a new glycoluril building block.
3.4 Synthesis and Reactivity of an Improved Glycoluril Building Block
The condensation of various benzil derivatives with p-methoxybenzylurea 84 27 produces
predominantly the cis-bis(PMB) protected glycoluril 28 (Scheme 15).85
This method, thus,
provides a means of producing a glycoluril capable of being substituted with an equimolar amount
of a corresponding electrophile, in a single step. This significant improvement over previous
84
85
Moschel, R. C.; Hudgins, W. R.; Dipple, A. J. Org. Chem 1986, 51, 4180-4185.
The unpublished results of Rebek, J., Jr.; et.al.
3. Synthesis
strategies has provided a means of producing large quantities of the previously mentioned
fragments - with PMB protection.
Scheme 15. Glycoluril Condensations using p-Methoxylbenzvlurea
0
0
H ArH
0
~NH2
+
H
MeO
27
TFA
Benzene, A
I
27
<NI
N)
PMB Ar PMB
(Major Product)
28
In order to utilize this approach, the new benzil 31 was synthesized which, unlike its aryl
ether counterpart, is insensitive to oxidations with cerium (IV) ammonium nitrate (CAN).
Oxidative removal of the PMB protecting group is carried out in good yields using the CAN
reagent. 86 Additionally, 31 (Scheme 16) is much more soluble than benzil itself in a variety of
organic solvents. The synthesis was initially attempted using a standard benzoin condensation87
however, these conditions produced none of the target benzoin. Various other methods can be
employed to carry out the benzoin condensation including several catalytic versions, 88as well as
certain umpolung89methods. The most successful method employed involved the formation of an
intermediate cyanobenzoate 9o 29. Upon deprotonation with potassium tert-butoxide 29 added to
the starting aldehyde to form a benzoin ester which, following hydrolysis, produced the benzoin 30
in good yield. 91 The benzoin was then oxidized to the corresponding benzil 31 in excellent yield, as
52
before, using CuSO 4.
Yoshimura, J.; Yamnaura, M.; Suzuki, T.; Hashimoto, H. Chemistry Letters 1983, 1001-1002. Yamaura,
M.; Suzuki, T.; Hashimoto, H.; Yoshimura, J.; Okamoto, T.; Shin, C.-G. Bull. Chem. Soc. Jpn. 1985, 58,
1413-1420. Riick, K.; Kinz, H. J. Prakt. Chem. 1994,336, 470-472.
87 Ide, W. S.; Buck, J. S. OrganicReactions 1948, Chapter5, 269-304.
88 Lappert, M. F.; Maskell, R. K. J.C.S. Chem. Comm. 1982, 580.
Breslow, R.; Kool, E. Letrahedron
Lett. 1988, 29, 1635-1638. Castells, J.; Lopez-Calahorra, F.; Domingo, L. J. Org. Chem 1988, 53, 44334436.
89 Albright, J. D. Tetrahedron 1983, 39, 3207-3233. William Lever, O., Jr. Tetrahedron 1976, 32, 194386
1971.
90
Seebach, D. Angew. Chem. Int. Ed. EngI. 1979, 18, 239-336.
Lantos, I.; Bender, P.E.; Razgaitis, K.A.; Sutton, B.M.; DiMartino, M.J.; Griswold, D.E.; Walz, D.T. J.
Med. Chem. 1984, 27(1), 72-75.
91 Modified
from: Rozwadowska, M. D. Tetrahedron 1985, 41, 3135-3140.
3. Synthesis
Scheme 16. Synthesis of PMB-Protected Glycoluril
CN
KCN
O
rYCHO
BzCl
TE BA
OBz
C
1
H20 / CH2CI2
(96%)
1)t-BuOK / THF
2) KOH /H20 / CH3CN
O
(82% - overall)
29
30
0
MeO
MGOJ
NH3
KNC
MeO
(93%)
Moir
CuS04
Pyridne
H20
(92%)
+
NH
HNH
H
97
31
TFA
Benzene
(62%)
H
.
O
R
N
N
H
*
N
NO
R=O<
PMB R PMB
32
The cis-protected glycoluril was then substituted with 1,4-dichloro-2-butene in quantitative
yield via a new procedure (Scheme 17). The yields of former substitution reactions had rarely
exceeded 50%, and using the former procedure this substitution was obtained in only 45%. From
this it was postulated that the strongly basic conditions (2 equivalents of base which were added to
form the dianion initially) were somehow decomposing the alkyl dihalide itself. Therefore, the
second equivalent of base was added simultaneously (and separately) with the dihalide using a
syringe pump.
Scheme 17. bis-PMB Protected Glycoluril Substitution Reaction
R
H
oI
O N
PMB
o+
N
R PMB
M
c,•
o,
CI
CI
PPMB
,.
DMSO
(>95%)
N.
N
O =<
O
N
N
R PMB
33
In producing the target diol using the olefin 33 it was anticipated that the successful
application of the \vet' Pr6vost could be utilized, thus producing the desired ct,o- stereochenmistry.
3 Svnthexi.~
However this attempt failed from two aspects (Scheme 18). First, the product having the same
stereochemistry 35 was produced predominantly (and, in fact, exclusively) using the Woodward
conditions. Second, the yield of the final product was very low. It is believed that the overall low
yield was due to PMB reactivity with iodine. In predicting the stereochemical outcome of such
dihydroxylations, relative to those performed using OsO4, it is not an exclusive rule that the
opposite stereochemistry is obtained. The complexity of this substrate has certainly disproven any
such rule.
Scheme 18. Woodward Reaction using bis-PMB Olefinic Fragnmnt.
HO
N
0 =<
N
1)12,AgOAc, HOAc
O0N'N1~2) H20, HOAc
PMB 'RPMB
RN
0=
3) KOH, MeOH
(-40%)
PM9
K2C03
0
N
R
OH
HO
OAc
MeOH
0
PM
PMB
0
1
R
PMB
35
34
As expected, the major product of the corresponding dihydroxylation with OsO4 was the
same diol 35 (Scheme 19). However, a most unexpected ratio of -8 to 1 was observed for this
substrate. Because of the interest in using the olefin 33 for the remaining studies (due to the PMB
stability under acidic conditions relative to the BOC group) further studies were undertaken to
produce the required fragments, in large scale, from this substrate.
Scheme 19. OsO4 Dihydroxylation using the bis-PMB Olefinic Fragment
HO
~Oso4
('7>)
0O<
NIN) N
N
PMB
R PMB
0
OH
(>7<
0S0 4
NO0
NMO
Acetone / 2O
=
(76%)
PMB
0
I
N
N
R
PMB
35
3.5 Functionalizations of the D,3-bis(PMB) Diolic Fragment
The diol 35 was examined as a building block for the formation of both the desired ,otdiol and the previously mentioned ot,Cx-diamine fragments in large scale. Having large quantities of
3. Synthesis
these compounds should permit the successful application of the various cyclization techniques
already explored (see section 3.3), as well as, the timely formation of several tetraimine
macrocycles of interest
Scheme 20. Functionalizations of the b,3-bis(PMB) Diolic Fragment based on Osmylation
HO
BzoH
OH
BzO
N
N
o =<NJNý=
0
R
PMB
BzOH
DEAD / PPh 3
N
N
0
N
PMB R
Toluene
PMB
OBz
(0%)
PMB
40
35
OMS
MSO
DBU
o
DMAP
CH2 C1
2
(trace)
T4
0
No
R PMB
PMB
37
0SO
0
N3
HO
0'
TsCI
NaN3
NN
NHMPA
N
(95%)
N+N
PMg
R PMB
PM9
R PMB
38
N3
N
N
CH 2 Cil2
4
o
PM
NaN 3
N3
e
N
0
o
PMB R PMB
R PMB
41
40
yields)
39
N3
a
NEt 3
DMAP
4~o
o
TsO
H2
Pd/C
NaOBz
DEAD / PPh 3
HO
NNH
N
2 2
0
1
0
PMg R PMB
42
H2N
3
ý
OBz
N N
R
Pd/C
o0
) 0
PMBR PMB
NIN
PMg
NH2
H2
PMB44
43
The first attempts to synthesize the desired ootx-diol involved the inversion of the P-diols
into the syn-bis(benzoate) compound 36 via a Mitsunobu reaction9 2 with benzoic acid (see Scheme
Mitsunobu, O.; Wada, M.; Sano, T. J. Am. Chem. Soc. 1972, 94, 679-680. Mitsunobu, O. Synthesis
1981, 1-28. Varasi, M.; Walker, K. A. M.; Maddox, M. L. J. Org. Chem 1987, 52, 4235-4238.
92
3. Synthesis
20).93 Due, apparently, to the hindrance of the mono-inverted intermediate, none of the product 36
was observed. Another approach involved the formation of the ,34-bis(mesylate) compound 37,
which could then be substituted with either carboxylic acid salts or nitrogen nucleophiles such as
sodium azide. Again, this attempt failed to produce a reasonable yield of the desired product
because of the steric hindrance.
At this point the emphasis was shifted to the cyclic sulfinyl compound 38, which was
produced quantitatively using thionyl chloride. 94 The sulfinyl moiety has been shown to be a better
leaving group than other groups such as the tosyl ester.95 Indeed, nucleophilic displacement of this
group using sodium azide produced the trans-azido alcohol 39 in excellent yield. Attempts were
then made to convert this into the corresponding anti-azido mesylate and tosylate 40. Although the
mesylate could not be formed in this manner, initial results with the tosylate seem positive. Thus
far, compound 40 has only been isolated in low yields; however, it is believed that a more
acceptable procedure can be devised for its production. This product could then be further
substituted with an azide to produce the xca-diazido compound 41, which can be readily converted
into the target diamine 44 using catalytic hydrogenation.
Another possibility which has not been explored involves inverting the anti-azido alcohol
39 to the corresponding syn-azido imide 43 via a Mitsunobu reaction. This approach has the
advantage that the two protected amines can be selectively deprotected using hydrazine and
catalytic hydrogenation.
The sulfinyl 38 was also reacted with sodium benzoate in an attempt to produce antibenzoate ester alcohol 42. However the initial results with this reaction are, at the writing of this
manuscript, inconclusive. Relating to this, the olefm 33 (Scheme 21) was epoxidized using mchloroperbenzoic acid (MCPBA) to attempt another synthesis of the desired a,c-diol. It has been
reported 96that, depending upon the stereochemistry of the product epoxide, such 'anti-Pr6vost' diols
93Bose, A. K.; Lal, B.; Hoffman, W.A., III; Manhas, M. S. LetrahedronLett. 1973, 18, 1619-1622.
94
95
96
Dauban, P.; Chiaroni, A.; Riche, C.; Dodd, R. H. J. Org. Chem 1996, 61, 2488-2496.
Guiller, A.; Gagnieu, C.H.; Pacheco, H. TetrahedronLett. 1985, 26, 6343.
Corey, E. J.; Das, J. LetrahedronLett. 1982, 23, 4217-4220.
3. Synthesis
can be produced. Although, based upon a similar analysis as in Figure 21, the epoxide of proper
stereochemistry was produced, the yields were unacceptable. These low yields are due, apparently,
to the PMB groups. Another idea was to displace the epoxide to form the anti-benzoate ester
alcohol 46. It is unclear whether a dynamic equilibrium will exist between the esters 46 and 42.
Such an equilibrium would certainly preclude the usefulness of any approach involving these antibenzoate ester alcohols.
Scheme 21. Functionalization of the bis(PMB) Olefinic Fragment via Epoxidation
O
BzO
PMd
0
R
CH2CI2
O =<
(16%)
(16%)
PM
O
HO
?
[
NaOBz
VMCPBA
0N
OH
O
O
OBz
R
O
O
NMB N
PMd R 6MB
N
N
PM9 R 6MB
N
N
PMI R 6MB
45
46
42
33
3.6 Progress Towards a New Glycoluril-Diene Fragment
One side-project which was undertaken during the other investigations involved an attempt
to generate the glycoluril-Diene fragment 47 (Figure 24). Such a diene was first suggested as one
means of affecting a cis-protection of the glycoluril (via cleavage of the olefins followed by
reductive or oxidative deprotection of the resulting carbonyl). With the advent of the new PMBbased technology discussed earlier, the need for such a compound, in this context, was eliminated.
However, this diene could be a rigid building block for the construction of new self-assembling
compounds via a Diels-Alder strategy. Compound 48 is one example of a concave building block,
which is potentially accessible via this approach.
ON
N
R o
Boc 47
D-A
NHN
HO
N
O "
R
NH
H
48
Figure 24. Anew glycoluril-diene fragment as a precursor to novel concave building blocks
3. Synthesis
57
In generating the bis-bromo fragment 50, which was expected to eliminate to the target
molecule, 97 bromination had to be carried out on the non-protected olefin 5 instead of the protected
versions due to the observed sensitivity of both the BOC and the PMB groups to oxidation.
Nonetheless, compound 50 was obtained in excellent yield in two steps (Scheme 22).
1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) 8 was then used to eliminate this compound under
relatively mild conditions. Unfortunately, the major product was the vinyl bromide 51. Such
reactivity is not uncommon for similar small to medium ring vicinal dihalides. 99 Although trace
amounts of the target diene had been isolated and classified using this reaction, the prospects of
obtaining large quantities of 47 seemed remote at this point.
Scheme 22. Elimination Strategy using Vicinal Dihalide and DBU
Br
Br
O
0i
R<
R
O...
cc
(>95%/)
Br
0=
NN
O
R
DA
THF=C4
O
(86%)
49
5
Br
Br
DBU
Boc20
N±N
Br
2
r
1.
, )
NTHF
ON
BoB
4R
NJ N
cBc
TF
O
R
50O
0=
N
T
Boc
(trace)
0
,NJiN>
0
N
N
51
(major product)
Another elimination strategy, which had been used in the literature,looinvolved forming the
allylic bromide using N-bromosuccinimide (NBS) and eliminating it with DBU as before. This
method minimizes the possibility of forming vinyl halides such as 51. The NBS reaction,
unfortunately, formed a complex mixture of products. However, the target 47 was clearly among
these products. Using this direct method, this compound has been produced with consistent yields
of around 12 %.
97 Wang, X. C.; Wong, H. N. C.; Mak, T. C. W. LetrahedronLett. 1987, 28, 5833-5836.
98 Wolkoff, P. J. Org. Chem 1982, 47, 1944-1948.
99 Bartsch, R. A. Chem. Rev. 1980, 80, 487-494.
10 Mehta, G.; Padma, S. J. Am. Chem. Soc. 1987, 109, 2212-2213.
3. Synthesis
Scheme 23. Production of Glycoluril-Diene Fragment Directly with N-Bromosuccinimide
(OR
0 <NtN >0
N
N
Boc RBo
R=(
-oCH)
- NBS
cat. perox.
=
N.pJ.
NIN>
N
N
CH2C2
BooR jo
(12%)
47
6
The low yield of this compound (above) is disappointing but it should not necessarily
prevent further studies into its synthesis and reactivity. This researcher has not done any further
work in this area.
3.7 Remarks
The purpose of this project was to design, synthesize and study flexible molecules, which
self-assemble into dimers in a similar manner to the original Tennisball'. Although this study is far
from complete, the insights gained from these synthetic challenges will, hopefully, assist other
members of the Rebek group in exploring the many aspects of 'flexibility' and 'metal-binding' which
were alluded to earlier in this report. More research is required in order to find adequate conditions
for the production of large quantities of the desired ox,x-diolic and (x,a-diamino fragments. Having
these substrates in adequate quantity will be the key to accessing and studying many interesting
macrocycles.
4. Experimental
4. Experimental
General Methods.
All commercially available compounds (Aldrich, Fluka) were used without further
purification unless otherwise indicated. CDCl 3 (99.8% D, Cambridge Isotope Laboratories) was used in all experiments as indicated. DMSO-d 6 (99.9% D, Cambridge Isotope
Laboratories) was used as indicated from freshly opened ampoules. 1H and 13C NMR
measurements were performed on the Bruker AC-250, Varian UN-300 and Varian VXR500 MHz instruments in the solvents indicated. Chemical shifts are reported as parts per
million (8) relative to tetramethylsilane.
Thin-layer chromatography was performed on Merck Silica 60 F254 precoated
TLC plates.
Thin-layer plates were stained using a solution composed of: 1L 10%
H 2SO 4 , 1 g CeSO 4 , 50 g (NH 4 ) 6Mo70
24 *4H2 0.
Flash chromatography was performed
01 Standard inert
using Merck Silica Gel 60 (230-400 mesh) according to Still et. al.o'
atomosphere techniques were used for syringe and cannula transfers of liquids and
solutions.
pp'-bis(methoxy)benzil (1).
Anisoin (27.2 g, 99.89 mmol) and copper(ll) sulfate pentahydrate (52.4 g, 210
mmol) were combined with 160 mL of pyridine and 100 mL of water. This mixture was
stirred into solution and refluxed for 12 hours.
Upon cooling, the mixture, which
crystallized throughout, was vacuum filtered and the filter cake was washed with 1N
aqueous HCI and water. The filter cake was vacuum dried to provide 25.0 g (93 %) of 1
as greenish crystals.
101
Still, W.C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923-2925.
4. Experimental
p,p'-dihydroxybenzil (2).
p,p'-bis(methoxy)benzil
(25 g, 92.5 mmol) was combined with pyridine
hydrochloride (42.8 g, 37.0 mmol) and this mixture was stirred and gently heated to
reflux. After 12 hours of gentle reflux the liquid was cooled and combined with enough
IN aqueous HC1 to affect precipitation. The precipitate was vacuum filtered and the filter
cake was vacuum dried to provide 21.68 g (97 %) of 2 as a yellowish amorphous solid.
p,p'-bis(hexyloxv)benzil (3).
p,p'-dihydroxybenzil (20 g, 82.6 mmol) and potassium tert-butoxide (19.5 g,
173.77 mmol) were dissolved in 250 mL of anhydrous DMF and this solution was heated
to reflux with vigorous stirring. To the refluxing mixture was dropped hexyl bromide
(24.4 mL, 173.82 mmol) over a 15 min period. This mixture was allowed to stir at reflux
for an additional 15 hours at which time it was combined with a mixture of 1 N aqueous
HC1 (300 mL) and 50:50 diethyl ether-hexane. Upon separation of the aqueous layer in a
separatory funnel the organic layer was washed with water (2X100 mL), iN NaOH (3X30
mL), water (100 mL) and brine (100 mL). The resulting organic layer was dried over
MgSO4 and concentrated in vacuo to provide 29.08 g (85.9 %) of 3 as a white solid. 'H
NMR (300 MHz, CDC13) 7.93 (d, J=6.9Hz, 4H), 6.95 (d, J=6.9Hz, 4H), 4.03 (t, J=6.6Hz,
4H), 1.80 (m, 4H), 1.46 (m, 4H), 1.35 (m, 8H), 0.91 (t, J=7.2Hz, 6H).
p,p'-bis(hexyloxvaryl)gycoluril (4).
p,p'-bis(hexyloxy)benzil (70.1 g, 171 mmol) was combined with urea (21.8 g, 363
mmol) and trifluoroacetic acid (36.2 mL, 469.84 mmol) in 600 mL of benzene.
This
mixture was refluxed for 24 hours with vigorous stirring and water removal (12 mL)
using a Dean-Stark apparatus. Upon cooling, the excess benzene was decanted from the
product residue, which was then combined with 1500 mL of ethanol and refluxed for 90
61
4. Experimental
min. The mixture was then cooled and vacuum filtered. The resulting filter cake was
oven-dried to provide 61.8 g (72 %) of 4 as a white amorphous solid.
p,p'-bis(hexyloxvaryl)Glycoluril-Substituted Olefin (5).
3.33 mmol Scale Reaction: Meticulously dried p,p'-bis(hexyloxyaryl)glycoluril (13.6 g, 27.5 mmol) was combined with 300 mL of anhydrous DMSO (dried
sequentially over 3A sieves), 250 mL of anhydrous THF and anhydrous pyridine (0.67
mL, 8.3 mmol) within a clean, dry round bottom flask. To this stirring mixture under
Argon was added potassium tert-butoxide (3.36 g, 30 mmol). After 10 min of stirring the
mixture became homogeneous and to it was dropped (over 60 min) a solution of 1,4dichloro-2-butene (0.35 mL, 3.33 mmol) in 25 mL of anhydrous DMSO. The mixture
was stirred for an additional 12 hours at which time it was combined with 350 mL of
0.1N aqueous HCl solution which affected immediate precipitation. The mixture was
vacuum filtered and the resulting filter cake was washed with 50 mL of water. The
filtrate was concentrated in vacuo (-THF) and the resulting heterogeneous aqueous
mixture was washed with ethyl acetate (3X200 mL). The resulting ethyl acetate solution
was saved for further workup. The filter cake was combined with 400 mL of ethyl acetate
and stirred for 15 min. After stirring the mixture was vacuum filtered. The filter cake
contained pure glycoluril which was saved for further use. The filtrate was combined
with the previous ethyl acetate solution, and the combined layer was washed with water
(5X200 mL) and brine (150 mL). The resulting solution was dried over MgSO4, and
concentrated in vacuo to yield a yellowish residue.
This residue was triturated with
diethyl ether and vacuum filtered. The filter cake was washed with diethyl ether and
dried under vacuum to provide 0.87 g (48 %) of 5 as a white amorphous powder: 1H
NMR (300 MHz, CDCl3) d 7.06 (d, J=8.7 Hz, 2H), 6.82 (d, J=8.7 Hz, 2H), 6.65 (d, J=9
Hz, 2H), 6.60 (d, J=9 Hz, 2H), 5.80 (m, 2H), 5.59 (s, 2H), 4.50 (dm, Jgem=16.2 Hz, 2H),
4. Experimental
3.83 (t, J=6.6 Hz, 2H), 3.81 (t, J=6.6 Hz, 2H), 3.57 (d, Jgem=16.2 Hz, 2H), 1.55-1.8 (m,
4H), 1.2-1.5 (m, 12H), 0.89 (t, J=6.9 Hz, 6H).
6.65 nmmol Scale Reaction: The reaction and workup were run in an identical
manner except that 0.7 mL (6.65 mmol) of 1,4-dichloro-2-butene was used to provide
1.098 g (30.2 %) of 5 as a white amorphous powder.
Bis(N-Boc)-p,p'-bis(hexyloxyaryl)glycoluril-substituted olefin (6).
p,p'-bis(hexyl-oxylaryl)Glycoluril-Substituted Olefin (1.665 g, 3.05 mmol), di-tbutyldicarbonate (2.0 g, 9.16 mmol) and 4-(N,N-dimethyl)aminopyridine (0.37 g, 3.03
mmol) were combined in 50 ml of anhydrous THF and stirred at 40_C for 12 hours. The
crude residue was purified using flash silica chromatography (40% ethyl actetate-hexane)
to provide 1.89 g (83%) of 6 as a clear residue. 0.38 Rf (tlc in 40% ethyl acetate-hexane).
1H
NMR (250 MHz, CDC13) d 6.74 (d, J=9 Hz, 2H), 6.62 (m, 4H), 6.47 (d, J=9 Hz, 2H),
5.80 (m, 2H), 4.53 (din, jgem=
17 .3
Hz, 2H), 3.85 (t, J=7.5 Hz, 2H), 3.81 (t, J=7.5 Hz, 2H),
3.61 (d, jgem= 1 7 .3 Hz, 2H), 1.6-1.6 (m, 4H), 1.2-1.5 (m, 30H), 0.90 (m, 6H).
Bis(N-Boc)-bis(butylester)glvcoluril- 3, -diolic (from initial classification studies):
HO
N
N
NMO
N
0= I
=0
N
Bog E Boc
NMO
Acetone / H2 0O
(58%E
(58%)
OH
N N
0 =NN
NIN
Bo" BooE
0
'800
(E = butylester )
A solution of the bis(N-Boc)-bis(butylester)glycoluril olefin (above)
(0.704 g,
1.185 mmol), osmium tetroxide (0.015 g, 5.9 ptmol), N-methylmorpholine-N-Oxide (0.18
g, 1.54 mmol) in 40 mL of acetone/water (2.5:1) was stirred under argon at room temp for
72 hr. The mix was concentrated in vacuo to yield crude solids. The crude solids were
purified using flash silica chromatography (MeOH/CHC13 5:95) to provide 0.429 g (58%)
4. Experimental
of purified product as a clear solid. 1H NMR (300 MHz, CDC13) 8 4.23-4.07 (m, 6H),
4.00-3.94 (dd, J=--4.5, 14.4 Hz, 2H), 3.43 (dd, J=6.6, 14.4 Hz, 1H), 3.0 (broad s, 2H), 1.701.60 (m, 4H), 1.53 (s, 18H), 1.43-1.34 (m, 4H), 0.97-0.89 (m, 6H);
NMR/DEPT (75
13C
MHz, CDCl 3) 6 164.7 (C), 163.7 (C), 163.2 (C), 162.8 (C), 152.5 (C), 152.2 (C), 148.7
(C), 138.0 (C), 132.6 (C), 131.1 (C), 129.0 (C), 84.6 (C), 80.1 (C), 78.7 (C), 71.7 (CH),
71.3 (CH), 68.3 (CH 2 ), 68.2 (CH 2), 67.8 (CH 2), 44.3 (CH 2), 43.0 (CH 2), 30.5 (CH 2 ), 30.4
(CH 2), 30.2 (CH 2), 29.1 (CH 2), 28.1 (CH 3 ),. 23.9 (CH 2), 19.3 (CH2 ), 19.2 (CH 2 ), 19.16
(CH2 ), 19.14 (CH 2), 14.2 (CH 3 ), 13.8 (CH 3), 11.1 (CH 3); HETCOR connectivities (75
MHz, CDC13) 8 (.4.23-4.07 'H)-(71.7, 71.3, 68.3, 68.2, 67.8, 44.3, 43.0
1H)-(44.3,
43.0 13C), (3.43 'H)-(44.3, 43.0 13C), (3.0 'H)-(44.3, 43.0
(30.5, 30.4, 30.2 13C), (1.53 'H)-(28.1
19.14
13C),
13 C),
13
13
C), (4.00-3.94
C), (1.70-1.60 'H)-
(1.43-1.34 'H)-(29.1, 23.9, 19.3, 19.2, 19.16,
(0.97-0.89 'H)-(13.8, 11.1 13C).
Bis(N-Boc)p,p'-bis(hexyloxyaryl)glvcoluril-f,3-diolic fragment (7).
Bis(N-Boc)-p,p'-bis(hexyloxyaryl)glycoluril-substituted
olefin
(1.48
g,
1.99
mmol), N-methylmrnorpholine-N-Oxide (0.304 g, 2.59 mmol) and osmium tetroxide (0.025
g, 0.098 mmol) were combined with 175 mL of acetone (reagent) and 70 mL of deionized
water.
This mixture was stirred at room tempurature for 3 hours.
At this time the
mixture was concentrated in vacuo and the resulting crude residue was purified using
flash silica chromatography (85% ethyl acetate-hexane) to provide 0.97 g (62%) of 7 as a
clear residue. 0.51 Rf (tlc in 100% ethyl acetate). 'H NMR (300 MHz, CDCl3) d 6.71 (d,
J=9 Hz, 2H), 6.61 (s, 4H), 6.47 (d, J=9 Hz, 2H), 4.1-4.3 (m, 4H), 3.86 (t, J=6.6 Hz, 2H),
3.81 (t, J=6.6 Hz, 2H), 3.12 (d, J=2.4 Hz, 2H), 3-3.07 (m, 2H), 1.6-1.8 (m, 4H), 1.2-1.5
(m, 30H), 0.8-1.0 (m, 6H).
The isomer 8 was obtained as a clear residue. 0.23 Rf (tic in 100% ethyl acetate).
1H NMR (300 MHz, CDC13) d 6.70 (d, J=9 Hz, 2H), 6.62 (s, 4H), 6.47 (d, J=9 Hz, 2H),
4. Experimental
4.22 (dd, Jgem=
15
Hz, Jvc=5.4 Hz, 2H), 3.83 (m, 6H), 3.27 (d, J=6.3 Hz, 2H), 3.10 (dd,
Jgem= 15 Hz, Jvc=2.7 Hz, 2H), 1.6-1.8 (m, 4H), 1.2-1.5 (m, 30H), 0.8-1.0 (m, 6H).
Bis(N-Boc)p,p'-bis(hexyloxyaryl)glycoluril-a-diolic fragment (8).
p,p'-bis(hexyloxyaryl)glycoluril-substituted
olefin (0.727 g, 1.33 mmol), N-
methylmorpholine-N-Oxide (0.20 g, 1.71 mmol) and osmium tetroxide (0.017 g, 0.067
mmol) were combined with 90 mL of acetone (reagent) and 35 mL of deionized water.
This mixture was stirred at 75 0 C for 90 min. At this time the mixture was concentrated in
vacuo and the resulting crude diolic residue was combined with di-t-butyldicarbonate
(1.74 g, 7.97 mmol) and 4-(N,N-dimethyl)aminopyridine (0.24 g, 1.96 mmol) in 50 mL of
anhydrous THF. This mixture was stirred at 40_C for 12 hours at which time it was
concentrated in vacuo to yield the dicarbonate/dicarbamate crude residue. This residue
was combined with anhydrous K2CO3 (0.06 g, 0.434 mmol) in 20 mL of anhydrous
methanol and stirred at room tempurature for approx. 12 hours. The mixture was then
concentrated in vacuo and the resulting residue was dissolved in ethyl acetate and washed
with water (2X20 mL) and brine (1X15 mL). The organic layer was then dried over
MgSO4 and concentrated to the product mixture residue. The residue was purified using
flash silica chromatography (85% ethyl acetate-hexane) to provide 0.308 g of 8 (30% - 3
steps) as a yellowish residue.
- see classification of 8 above -
Benzyl 2-carboxyl-6-pyridinoate (14).
2,6-pyridine dicarboxylic acid (3.0 g, 17.95 mmol) was combined with 1.0M
tetrabutylammonium fluoride (36 mL, 36 mmol) in 100 mL of THF (reagent). To this
stirring solution was dropped (over 2 hours) a solution of benzyl bromide (2.14 mL, 18.0
mmol) in 25 mL of THF. The mixture was stirred an additional 12 hours at which time it
4. Experimental
was concentrated in vacuo to yield a thick, clear liquid which was combined with 50 mL
of ethyl acetate and washed with 1.2 N HC1 (3X15 mL) and water (3X15 mL). The
organic layer was then extracted with 5% NaHCO3 (3X15 mL). The aqueous basic layer
was then washed with ethyl acetate (15 mL), combined with 100 mL of ethyl acetate and
washed with 1.2 N HCI (2X20 mL) and brine (50 mL). The resulting organic layer was
dried over MgSO4 and concentrated in vacuo to provide the crude acid mixture as a white
powder.
This
mixture was then purified using flash silica chromatography (15%
methanol-chloroform) to provide 1.303 g (26.3%) of 14 as a white powder:
0.14-
0. 3 7 streak Rf (tlc in 25% methanol-chloroform). 1H NMR (300 MHz, CDC13) d 9.1-11.3
(broad s, 1H), 8.41 (d, J=7.8 Hz, 1H), 8.37 (d, J=7.8 Hz, 1H), 8.11 (t, J=7.8 Hz, 1H), 7.37.55 (min, 5H), 4.45 (s, 2H).
Dibenzyl ester 3-fragment (15).
Benzyl 2-carboxyl-6-pyridinoate (0.519 g, 1.88 mmol) was combined with oxalyl
chloride (0.25 ml, 2.87 mmol) and 0.5% (v/v) DMF in DCE (0.1 mL, catalytic) in 30 mL
of anhydrous methylene chloride. This mixture was stirred at room temp under Ar for 12
hours.
At this time the mixture was concentrated in vacuo
and combined with
triethylamine (0.44 mL, 3.16 mmol) and Bis(N-Boc)p,p'-bis(hexyloxyaryl)glycoluril-bdiolic fragment (0.49 g, 0.63 mmol) in 30 mL of DCE. This reaction mixture was stirred
for 2 hours, concentrated and the resulting residue purified using flash silica
chromatography (70% ethyl acetate-hexane) to provide 0.674 g (85.3 %) 15 as a clear
solid: 0.53 Rf (tlc using 5% methanol-chloroform). 1H NMR (300 MHz, CDC13) d 8.13
(d, J=7.8 Hz, 2H), 7.70 (t, J=7.8 Hz, 2H), 7.56 (d, J=7.8 Hz, 2H), 7.29-7.43 (min, 10H),
6.69 (d, J=9 Hz, 2H), 6.52 (d, J=9 Hz, 2H), 6.45 (d, J=9 Hz, 2H), 6.38 (d, J=9 Hz, 2H),
5.69 (t, J=5.2 Hz, 2H), 5.37 (min, 4H), 4.56 (dd, jgem= 1 5 Hz, Jvic=4.8 Hz, 2H), 3.80 (t,
J=6.3 Hz, 2H), 3.73 (dd, Jgem= 1 5 Hz, Jvic=6.3 Hz, 2H), 3.51 (t, J=6.6 Hz, 2H), 1.5-1.85
(min,
4H), 1.2-1.5 (min, 30H), 0.8-1.0 (min, 6H).
.
EXDe
Ex
4
p
ire
mental
Diacidic -fragment (16).
Dibenzyl ester P-fragment (0.63 g, 0.501 mmol) was combined with 10% Pd/C
(0.5 g) in 50 mL of anhydrous ethanol. Through this mixture was bubbled dry hydrogen
gas for 5 hours. The mixture was then allowed to stir for an additional 8 hours under
hydrogen. At this time the mixture was filtered through Celite and concentrated in vacuo
to provide 0.49 g (91%) of 16 as a clear solid: 'H NMR (500 MHz, DMSO) d 8.14 (d,
J=8 Hz, 2H), 7.94 (t, J=8 Hz, 2H), 7.55 (d, J=8 Hz, 2H), 6.64 (d, J=9Hz, 2H), 6.60 (d,
J=9 Hz, 2H), 6.53 (d, J=9 Hz, 2H), 6.48 (d, J=9 Hz, 2H), 5.58 (t, J=5.5 Hz, 2H), 4.42 (dd,
jgem= 1 5 Hz, Jvc=4.5 Hz, 2H), 3.81 (t, J=6.5 Hz, 2H), 3.62 (dd, jgem= 1 5 Hz, Jvic=5.5 Hz,
2H), 3.53 (t, J=6.5 Hz, 2H), 1.5-1.7 (m, 4H), 1.2-1.5 (m, 30H), 0.8-0.9 (m, 6H).
Dibromoacetyl ester 3-fragment (20).
To a solution of bromoacetyl bromide (77 mL, 0.854 mmol), 2,6-lutidine (0.2 mL,
1.72 mmol) and a trace of 4-(N,N-dimethylamino)pyridine in 15 mL of anhydrous toluene
at 0_C was slowly added Bis(N-Boc)p,p'-bis(hexyloxyaryl)glycoluril-b-diolic fragment
(0.265 g, 0.34 mmol). This heterogeneous mixture was then stirred at room temp for 12
hours at which time it was concentrated in vacuo and the resulting residue purified using
flash silica chromatography (40% ethyl acetate -hexane) to provide 0.279 g (80.2%) of 20
as a clear solid. 0.45 Rf (tlc using 40% ethyl acetate in hexane). 'H NMR (250 MHz,
CDC13) d 6.71 (d, J=9 Hz, 2H), 6.66 (d, J=9 Hz, 2H), 6.54 (d, J=9 Hz, 2H), 6.48 (d, J=9
Hz, 2H), 5.29 (t, J=5.7 Hz, 2H), 4.32 (dd, Jgem= 1 5 Hz, Jvc=5 Hz, 2H), 3.87 (t, J=6.5 Hz,
2H), 3.81 (t, J=6.5 Hz, 2 H), 3.40 (m, 6H), 1.65-1.8 (m, 4H), 1.2-1.5 (m, 30H), 0.8-1.0
(m, 6H).
4. Experimental
Bis(N-Boc)p,p'-bis(hexyloxyaryl)glycoluril-dibromo fragment (49).
p,p'-bis(hexyloxyaryl)Glycoluril-Substituted Olefin (0.25 g, 0.458 mmol) was
combined with 15 mL of carbon teterachloride and to this heterogeneous mixture was
added bromine (23 mL, 0.449 mmol). The mixture was then stirred for 12 hours at room
temp, and concenxtrated in vacuo to reveal the crude product (0.329 g). This residue was
then combined with di-t-butyldicarbonate
(0.15 g, 0.687 mmol)
and 4-(N,N-
dimethyl)aminopyridine (0.028 g, 0.229 mmol) in 15 mL of anhydrous THF and stirred at
40_C for 12 hours. At this time the mixture was concentrated in vacuo and the resulting
residue purified using flash silica chromatography (40% ethyl acetate-hexane) to provide
0.36 g (95%) of 49 as a clear solid. 0.26 Rf (tlc using 30% ethyl acetate-hexane). 'H
NMR (250 MHz, CDC13) d 7.18 (d, J=8.75 Hz, 1H), 7.10 (dd, J'=8.75 Hz, J"=2.5 hz,
1H), 6.82 (dd, J'=8.75 Hz, J"=2.5 Hz, 1H), 6.68 (d, J=8.75 Hz, 1H), 6.46 (dd, J'=9 Hz,
J"=2.75 Hz, 1H), 6.30 (s, 2H), 6.17 (dd, J'=8.75 Hz, J"=2.5 Hz, 1H), 4.99 (t, J=8 Hz,
1H), 4.5-4.7 (m, 2H), 4.31 (dd, jgem=15 Hz, J•c=6.5 Hz, 1H), 3.7-3.9 (m, 4H), 3.54 (d,
Jgem= 1 5
Hz, 1H), 3.17 (dd, Jgem=
15
Hz, Jvic=10 Hz, 1H), 1.6-1.8 (m, 4H), 1.2-1.6 (m,
30H), 0.8-1.0 (m, 6H).
p-isopropylcyanobenzoate (29):
4-isopropylbenzalde (15 mL, 99.0 mmol), benzyl triethylammonium chloride
(2.93 g, 12.9 mmol) and potassium cyanide (25.76 g, 395.6 mmol) were combined with
110 mL of deionized water and 100 mL of methylene chloride. To this mixture was
dropped a solution of benzoyl chloride (13.8 mL, 120 mmol) in 70 mL of methylene
chloride over a period of 30 min. After an additional 30 min of stirring the resulting
mixture was transferred to a separatory funnel and the two layers were separated. The
organic layer was then washed with 5% (w/w) K2CO3 (3X30 mL), water (2X200 mL)
and 50 mL brine. The resulting organic solution was dried over anhydrous MgSO4,
gravity filtered and evaporated in vacuo to reveal 29 as a reddish solid: 26.5 g (96%),
4. Experimental
0.45 Rf (20% Ethyl Acetate-Hexane).
'H NMR (250 MHz, CDCl 3 ) 8.07 (d, J=7.2Hz,
2H), 7.65-7.43 (m, 5H), 7.33 (d, J=7.2Hz, 2H), 6.65 (s, 1H), 2.95 (m, 7.5Hz, 1H), 1.27 (d,
J=7.5Hz, 6H).
p,p'-bis(isopropyl)benzoin (30):
CyanoBenzoate, 29, (26.55 g, 95.2 mmol) and 4-isopropybenzaldehyde (14.5 mL,
95.6 mmol) were combined within 250 mL of anhydrous THF. To this stirring solution
under Ar was dropped a solution of potassium tert--butoxide (11.5 g, 102.5 mmol) in 100
mL of anhydrous THF over approx. 45 min. The resulting mixture (now dark) was stirred
for an additional 2 hours at which time it was evaporated in vacuo and the resulting oil
was combined with 300 ml of ethyl acetate. This solution was washed with water (2X50
mL) and brine (2X50 mL). The resulting solution was then dried over MgSO4, gravity
filtered and evaporated in vacuo to reveal an orange solid: 36.98 g (97%) - a-benzoate
ketone, 0.53 Rf (20% Ethyl Acetate-Hexane). This solid was combined with 750 mL of
CH3CN and to it was dropped a solution of potassium hydroxide (10.4 g, 185.4 mmol) in
150 mL of water over a period of 30 min. The mixture was then stirred for an additional
15 hours at which time it was acidified using appro)x. 75 mL of 2.4N HC1 and evaporated
in vacuo (- CH3CN). This mixture was then combined with 250 mL of diethyl ether and
the organic layer was washed with 1N NaOH (4X50 mL), 100 mL of water and 50 mL of
brine. The resulting ether layer was dried over MgSO4, gravity filtered and evaporated in
vacuo to yield 30 as a yellow solid: 23.02 g (82%), 0.36 Rf (20% Ethyl Acetate Hexane). 'H NMR (300 MHz, CDC13) 7.87 (d, J=6.6Hz, 2H), 7.27-7.24 (m, 4H), 7.19 (d,
J=6.6Hz, 2H), 5.90 (d, J=6.3Hz, 1H), 4.52 (d, J=6.3Hz, 1H), 2.93-2.83 (m, 2H), 1.231.18 (m, 12H).
4. Experimental
p,p'-bis(isopropyl)benzil (31):
Benzoin, 2, (23.02 g, 77.8 mmol) and CuSO4-5H20 (40.78 g, 163.33 mmol) were
combined in 125 mL of pyridine and 80 mL of water. This mixture was then refluxed for
18 hours and the reaction mixture was evaporated in vacuo
(-pyridine).
This
heterogeneous mixture was then combined with 250 mL of diethyl ether and the ether
layer was washed with 100 mL of water, IN HCI (2X50 mL) and 50 mL of brine. The
resulting organic layer was then dried over MgSO4, gravity filtered and evaporated in
vacuo to reveal a yellowish solid: 21.1 g (92.2%).
1H
NMR (250 MHz, CDCl 3) 7.86 (d,
J=7.5Hz, 4H), 7.36 (d, J=7.5Hz, 4H), 2.98 (m, J=7.5Hz, 2H), 1.28 (d, J=7.5Hz, 12H).
p-methoxvbenzylurea (27):
p-Methoxybenzylamine (25 mL, 191.4 mmol) was combined with 600 mL of
deionized water. This heterogeneous solution was then slightly acidific using 12N HC1
(14 mL) and IN HCI (-~25 mL). The mixture becomes cloudy and then homogenous
upon acidification. To this stirring solution at room temp. was dropped a solution of
potassium cyanate (23.29 g, 287.11 mmol) in 200 mL of water over approx. 30 min.
After 24 hours of stirring the solution (now heterogeneous) was vacuum filtered, and the
filter cake was dried to yield 32 g (93%) of 27 as a clean white solid.
cis-bis(PMB)-p,p'-bis(isopropvl)phenvylglycoluril (32):
To a solution of 31 (21.1 g, 71.8 mmol) and 27 (26 g, 144.4 mmol) in 250 mL of
benzene was added TFA (14.0 mL, 181.7 mmol). This stirring solution was then refluxed
with water removal using a dean-stark apparatus for 24 hours. At this point the benzene
was removed in vacuo, and the resulting solids were triturated in methanol (using
sonication) prior to being vacuum filtered. The filter cake was then dried to reveal 27.27
g of 31 (61.5%) as a white powder. 1H NMR (300 MHz, DMSO) 8.23 (s, 2H), 7.16 (d,
4. Exverimental
J=8.7Hz, 4H), 6.92-6.77 (m, 10H), 6.54 (d, J=8.4Hz, 2H), 4.32 (d, J=16.5Hz, 2H), 3.81
(d, J=16.5Hz, 2H), 3.72 (s, 6H), 2.72-2.64 (m, 2H), 1.02 (t, J=6.9Hz, 12H).
mono-(TBDMS)protected-D, -diolic fragment (23):
To a solution of 7 (0.275 g, 0.353 mmol), DBU (63ptL, 0.42 mmol) and DMAP
(0.022 g, 0.180 mmol) in 20mL of anhydrous toluene was added a standard solution of
TBDMSCI in THF (0.36 mL of 1.0M soln., 0.36 mmol). This mixture was stirred as such
under Ar for approx. 16 hours. At this time the mixture was evaporated in vacuo, and the
resulting residue was purified using flash silica chromatography (30% ethyl acetate hexane) to provide 0.269 g (85.2%) of 23 as a clear foam. 0.21 Rf (tlc using 30% ethyl
acetate - hexane). 1H NMR (300 MHz, CDC13 ) 8 6.89-6.387 (m, 8H), 4.17 (broad s, 1H),
4.02-3.95 (m, 2H), 3.87-3.78 (m, 4H), 3.05 (dd, J'=O10Hz, J"=15.6Hz, 1H), 2.88 (dd,
J'=10Hz, J"=17.7Hz, 1H), 2.55 (d, J=2.7Hz, 1H), 1.75-1.66 (m, 4H), 1.46-1.33 (m, 30H),
0.898 (m, 6H), 0.838 (s, 9H), 0.185 (s, 3H), 0.131 (s, 3H).
mono-(TMS)protected-5,D-diolic fragment (24):
To a solution of 7 (0.22 g, 0.282 mmol), DBU (51.tL, 0.341 mmol) and DMAP
(0.017 g, 0.1390 mmol) in 20mL of anhydrous toluene was added a standard solution of
TMSC1 in THF (0.28 mL of 1.0M soln., 0.28 mmol). This mixture was stirred as such
under Ar for approx. 16 hours. At this time the mixture was evaporated in vacuo, and the
resulting residue was purified using flash silica chromatography (40% ethyl acetate hexane) to provide 0.151 g (63%) of 24 as a clear foam. 0.29 Rf (tlc using 40% ethyl
acetate - hexane). 1H NMR (300 MHz, CDCl 3) 6 6.85-6.40 (m, 8H), 4.2-4.1 (m, 2H), 4.13.95 (m, 2H), 3.87-3.78 (m, 4H), 3.04 (dd, J'=10Hz, J"=15.6Hz, 1H), 2.89 (dd, J'=10Hz,
J"=17.7Hz, 1H), 2.54 (d, J=2.7Hz, 1H), 1.8-1.6 (m, 4H), 1.46-1.33 (m, 30H), 0.898 (m,
6H), 0.838 (s, 9H), 0.14 (s, 9H).
4. Exverimental
bis[mono-(TMS)protected-D,W-diolic fragment]oxalate (25):
To a solution of 24 (0.258 g, 0.303 mmol) and triethylamine (51 tL, 0.366 mmol)
in 10 mL anhydrous toluene was added oxalyl chloride (15 pL, 0.172 mmol). This
solution was stirred under Ar at 500 C for approx. 2 hours. At this point the reaction
mixture was evaporated in vacuo, and the resulting residue was purified using flash silica
chromatography (30% ethyl acetate - hexane) to yield 82 mg (31% - both isomers) of a
mixture of 25 and its diastereomer (unseparable) as a clear foam. 0.52-0.60 Rf (tlc using
40% ethyl acetate - hexane). 'H NMR (300 MHz, CDCl 3) 6.81-6.35 (m,8H), 5.2-5.0 (m,
1H), 4.1-4.0 (m,3H), 3.863 (t, J=6.6Hz, 2H), 3.80 (t, J=6.6Hz, 2H), 3.33-3.17 (m,2H),
1.8-1.6 (m,4H), 1.5-1.2 (m,30H), 0.94-0.88 (m,6H).
bis(PMB) Olefinic Fragment (33):
To a solution of 32 (2.017 g, 3.26 mmol) in anhydrous DMSO was added t-BuOK
(0.38 g, 6.77 rnmol).
To this solution under Ar, after 10 min. of stirring, was
simultaneously syringed (in separate syringes) a solution of 1,4-dichloro-2-butene (0.38
mL, 3.61 mmol) in 10 mL of anhydrous DMSO and a solution of t-BuOK (0.38 g, 6.77
mmol) in 10 mL of anhydrous DMSO, over approx. 2 hours. The reaction mix was
stirred under Ar as such for 12 hours at which time it was combined with 300 mL of a
dilute HC1 solution (50 mL of 2.4N HC1 added to 250 mL of water). This mixture was
then washed with ethyl acetate (4X50 mL) and the ethyl acetate washings were combined.
The combined organic washings were washed with water (6X200 mL) and 100 mL of
brine before being dried over anhydrous MgSO 4 .
The filtered solution was then
evaporated in vacuo to yield 2.278 g (-100%) of 33 as a clear foam.
1H
NMR (250
MHz, CDC13) 7.10 (d, J=8.75Hz, 4H), 6.89-6.59 (m, 12H), 5.92-5.90 (m,2H), 4.7-4.5
(md, 2H), 4.41 (d, J=15Hz, 2H), 3.91 (d, J=15Hz, 2H), 3.77-3.5 (m,10H), 2.8-2.55 (m,
2H), 1.1-1.07 (m,12H).
4. Experimental
bis(PMB) 3,D-diolic fragment (35):
To a solution of 33 (0.695 g, 1.04 mmol) in 90 mL of acetone and 35 mL of
deionized water were added N-methylmorpholine N-oxide (0.16 g, 1.37 mmol), and
osmium tetroxide (0.013 g, 0.051 mmol). This mixture was then stirred overnight at
room tempurature, at which time is was concentrated in vacuo, and the resulting residue
was purified using flash silica chromatography (75% ethyl acetate - hexane) to provide
0.561 g (76.6%) of 35 as clear foam. 0.15 Rf (tlc using 75% ethyl acetate - hexane).
1H
NMR (300 MHz, CDCl 3) 7.09 (d, J=8.7Hz, 4H), 6.9-6.61 (m, 12H), 4.38 (d, J=16.2Hz,
2H), 4.35-4.15 (m, 4H), 3.93 (d, J=16.2Hz, 2H), 3.78 (s, 6H), 3.13 (dd, J'=8.1Hz,
J"=14.7Hz, 2H), 2.8-2.6 (m,2H), 2.59 (d, J=5Hz), 1.08 (m,12H).
bis(PMB) [,D-sulfinyl fragment (38):
To a solution of 33 (0.25 g, 0.355 mmol) and triethylamine (0.2 mL, 1.43 mmol)
in 15 mL of anhydrous THF under Ar, at -25 0 C (via CO2/CC14 bath), was added a
solution of thionyl chloride (52 kL, 0.713 mmol) over approx. 15 min. The solution was
then stirred for an additional 45 min at which time it was evaporated in vacuo, and the
resulting residue was purificed using flash silica chromatography (30% ethyl acetate hexane) to yield 0.256 g (96.2 %) of 38 as a mixture of diastereomers. 0.28 Rf (tlc using
30% ethyl acetate - hexane). 1H NMR (250 MHz, CDC13) 7.07 (d, J=8.25Hz, 4H), 6.96.5 (m, 12H), 5.6-5.5 (m,1H), 5.3-5.2 (m, 1H), 4.55-4.3 (m,4H), 4.0-3.7 (m,2H), 3.80
(s, 6H), 3.6-3.35 (m,2H), 3.15-3.0 (m,2H), 2.8-2.6 (m,2H), 1.2-1.0 (m,12H).
bis(PMB) anti-azido alcoholic fragment (39):
To a solution of 38 (0.256 g, 0.341 mmol) in 7 mL of anhydrous HMPA was
added sodium azide (0.067 g, 1.03 mmol). The mixture was then stirred under Ar at
100 0 C for 2 days. At this point the mixture was combined with 200 mL of water, and this
4~ Frnprirnental
mixture was washed with ethyl acetate (3X50 mL). The combined organic washings
were washed with water (6X50 mL) and 50 mL of brine prior to drying over anhydrous
MgSO4. The dried solution was then evaporated in vacuo to yield 0.255 g (96%) of 39 as
a clear foam. 0.52 Rf (tlc using 75% ethyl acetate - hexane). 1 H NMR (250 MHz,
CDC13) 7.19 (d, J=8.75Hz, 2H), 7.09 (d, J=8.75Hz, 2H), 7.0-6.3 (m, 12H), 4.82 (d,
J=16.5Hz, 1H), 4.3-4.15 (m,3H), 4.05-3.9 (m,3H), 3.78 (s, 3H), 3.77 (s, 3H), 3.61 (q,
J=3.75Hz, 1H), 3.44 (dd, J'=3.75Hz, J"=15Hz, 1H), 2.96 (dd, J'=O10Hz, J"=16Hz, 1H),
2.68 (m,2H), 2.26 (d, J--4.25Hz, 1H), 1.2-1.0(m, 12H).
bis(PMB) x,ax-epoxide fragment (45):
The olefinic fragment 33 (0.5 g, 0.746 mmol) and MCPBA (0.52 g, 3.01 mmol)
were reacted in a solution of 10 mL of chloroform at room temp for approx. 6 hours. At
this point the reaction mixture was evaporated in vacuo and the resulting residue was
purified using flash silica chromatography (70% ethyl acetate - hexane) to yield 0.082 g
(16%) of 45 as a clear foam. 0.35 Rf (tlc using 75% ethyl acetate - hexane). 1H NMR
(300 MHz, CDC13) 7.15 (d, J=8.4Hz, 4H), 6.87 (d, J=8.1Hz, 2H), 6.82 (d, J=9Hz, 4H),
7.32 (d, J=8.1Hz, 2H), 6.66 (d, J=9Hz, 2H), 6.57 (d, J=8.4Hz, 2H), 4.76 (dt, J'=2.4Hz,
J"=16.2Hz, 2H), 4.43 (d, J=16.2Hz, 2H), 3.86 (d, J=16.2Hz, 2H), 3.71 (s, 6H), 3.32 (d,
J=16.2Hz, 2H), 3.14 (t, J=2.4Hz, 2H), 2.8-2.6 (m,2H), 1.1-1.06 (m,12H).
bis(BOC) glycoluril-diene fragment (47):
The fragment olefin 6 (0.296 g, 0.397 mmol), N-bromosuccinimide (0.071 g,
0.399 mmol) and a trace of benzoyl peroxide were combined in 15 mL of anhydrous
methylene chloride and refluxed for 6 hours. The mixture was then evaporated in vacuo
and the resulting residue was purified using flash silica chromatography (20% ethyl
acetate - hexane) to yield 0.036 g (12.2%) of 47 as a clear residue. 0.62 Rf (tlc using 40%
ethyl acetate - hexane). 1H NMR (250 MHz, CDCD 3) 6.82 (d, J=9Hz, 2H), 6.74 (dd,
74
4. Experimental
J'=3Hz, J"=6.6Hz, 2H), 6.63 (d, J=9Hz, 2H), 5.20 (dd-'batman', J'=3Hz, J"=6.6Hz, 2H),
3.8 (dt, J'=2.1Hz, J"=6.6Hz, 4H), 1.8-1.6 (m,4H), 1.5-1.2 (m,30H), 1.0-0.8 (m,6H).
every medicine is an innovation; and he that will not apply
new remedies much expect new evils; for time is the greatest innovator;
and if time of course alter things to the worse, and wisdom and counsel
shall not alter them to the better, what shall be the end?'
S...Surely
Bacon, 1625