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TOPIC: PREFUNCTIONALIZED AND ITERATIVE SYNTHESIS
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1
Iterative synthesis
1.1
Introduction
Iterative synthesis is the stepwise synthesis of molecules consisting repeated building blocks by using the
repeated succession of similar reaction sequences (from Latin: iterare, iterum - again).
Vögtle Top. Cur. Chem. 1998, 197, 1
Iterative strategy plays an importance role in biosynthesis of complex molecules. For example, the assembly
of acyl units by sequential Claisen condensation to form fatty acids. Polypeptides are built from the repetitive
amidation of amino acids in ribosomes. In the same fashion, oligonucleotides are derived from nucleotide
monomers; oligosaccharides from sugar units. Also, most of small-molecule natural products are the results
of iterative synthesis from smaller building blocks: polyketides from malonyl-CoA or methylmalonyl-CoA,
non-ribosomal peptides from aminoacids, polyterpens from isoprenes, …
Using nature as model, chemists have studied and established iterative and automated synthesis for not only
biopolymers (polypeptides, oligonucleotides, oligosaccharides), but also organic polymers, natural products,
and small molecules.
1.2
Strategies
1.2.1 Basic steps
Generally, there are two steps for iterative synthesis:
(1) coupling
(2) activation/deprotection
Iterative synthesis sequence:
In controlled iterative reactions, bi- and multifunctional building blocks are employed that contain only one
reactive functional group (“ON”), while all other groups are unreactive (“OFF”) thereby suppressing
uncontrolled polymerization. After the selective coupling of the reactive group, another, previously
unreactive functional group is activated/deprotected (“ON”) and the coupling sequence repeated, thus
allowing the efficient formation of defined oligomers from readily available building blocks. This enables even
non-experts to synthesize complex molecules in a short time, and promotes the rapid investigation and
application of these compounds in chemistry and biology.
Glorius ACIE 2009, 48, 5240
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1.2.2 Ideal iterative synthesis
(1) Building blocks and their derivatives should be readily available and inexpensive
(2) All steps in iterative steps are high yielding, are tolerant of many different functional groups, and do not
require nor produce toxic compounds
(3) Easy handling and facile separation or purification
(4) Iterative coupling sequences are reliable and predictable
(5) The sequence is suitable for solid phase synthesis and automation
Glorius ACIE 2009, 48, 5240
2
Polypeptide synthesis
2.1
Biosynthesis – Ribosomal polypeptide synthesis
Polypeptides are built by sequential amide formation reactions happening in the ribosomes, in which the
initial amino acid is lengthened by another amino acid per reaction cycle. Contrary to peptide synthesis
(discussed below), the peptide chain is grown from the C-terminal in ribosome.
Aqvist PNAS 2005, 102, 12395
2.2
Polypeptide synthesis
The amide bond is the key chemical connection of peptides and its synthesis is one of the most important
reactions in organic chemistry. The amide bond is commonly formed by condensation of the carboxylic acid
part of one amino acid with the amine function of another amino acid. For successful coupling the carboxylic
acid has to be converted into an activated species (e.g. acid chloride).
2.2.1 Building blocks
The building blocks for peptide synthesis are amino acids (see also lecture 4 “amino acids synthesis”). The
proteogenic amino acids are normally obtained by fermentation from microorganisms. Protected amino acids
are commercially available from several companies (e.g. Bachem).
2
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2.2.2 Solution phase
The first synthesis of a dipeptide was achieved by Emil Fischer. Refluxing of 2,5-diketopiperazine (“glycine
anhydride”) in concentrated HCl provided glycylglycine. The work of Curtius with diazo compounds led to the
first practical method for peptide synthesis.
Fischer Ber. Deutsch. Chem. Ges. 1901, 34, 2868
Curtius J. Prakt. Chem. 1904, 70, 57
The major problems at this time stemmed from the difficulties in obtaining pure L-amino acids and the
absence of an easily removable amino-protecting group.
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The introduction of the carbobenzoxy group (Cbz) for the temporary protection the amino function by
Bergmann and Zervas solved part of the problem and numerous small peptides could be synthesized in a
predictable manner (e.g. synthesis of Oxytocin by du Vigneaud).
Bergmann Ber. Deutsch. Chem. Ges. 1932, 65, 1192
Du Vigneaud JACS 1953, 75, 4879
2.2.3 Solid phase
The development of solid phase peptide synthesis (SPPS) by Merrifield revolutionized the field of peptide
chemistry. Today, SPPS is acknowledged as the method of choice for creating peptides in a synthetic
manner. In the most common strategy the C-terminus of an amino acid (with protected side chain and Nterminus) is immobilized on a solid support (e.g. cross-linked polystyrene resin). Then the amino protecting
group is removed and coupled to a second fully protected amino acid with an activated carboxyl group. This
process of deprotection and coupling is repeated until the desired sequence is achieved. Final side chain
deprotection and cleavage from the resin yield the free peptide.
Merrifield JACS 1963, 85, 2149
For SPPS it is important to choose the correct protecting group strategy. During the several deprotection
steps of the N-termini the protecting groups of the amino acid side chains have to stay untouched
(orthogonality of protecting groups) and the peptide must not be cleaved from the resin. Today, there are two
major strategies: The Fmoc and the Boc-strategy.
Cleavage
Advantages
Disadvantages
Boc cleaved under acidic conditions (TFA in
CH2Cl2). Cbz group of side chains and resin (e.g.
Merrifield resin) stable to TFA, normally cleaved by
treatment with very strong acids.
Boc-protected amino acids normally cheaper.
Repetitive treatment with TFA prevents peptide
aggregation (increased solubility)
In Boc strategy the final deprotection of side chains
and cleavage from resin require gaseous HF (very
corrosive and dangerous, special equipment!).
4
Fmoc cleaved under basic conditions
(Piperidine in DMF). Boc deprotection and
cleavage from resin (e.g. Wang resin) with
TFA in CH2Cl2.
Fmoc strategy allows for milder deprotection
scheme and is considered truly orthogonal.
No special equipment needed.
Peptide aggregation can be a problem,
especially when peptide sequence consists
of several hydrophobic amino acid residues.
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Since its introduction 40 years ago SPPS was substantially optimized. New linkers, side chain protecting
groups and activating groups for the carboxylic acid have improved the overall method and SPPS can be
considered as a fully automated process (peptide synthesizer).
Reviews: Merrifield Protein Science 1996, 5, 1947
Seebach J. Pept. Science 2005, 65, 229
3
Polynucleotide (RNA/DNA) synthesis
3.1
Biosynthesis
- Polynucleotides are biopolymers composed of 13 or more nucleotides as monomers. DNA and RNA are
examples of polynucleotides. Polynucleotides are biosynthesized via replication or transcription of DNA.
- A single nucleotide consists of a phosphorylated deoxyribose (for RNA: ribose) unit that is attached at the
1’-position to a nucleobase. For DNA/RNA synthesis all the building blocks (with different protecting groups)
are commercially available.
5
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3.2
Polynucleotide synthesis
The publication of Watson and Crick on the structure of DNA can be considered as one of the most
important publications of the twentieth century. Since then many laboratories became interested in
nucleoside chemistry and different approaches to synthetic polynucleotides were introduced.
Watson and Crick Nature 1953, 171, 737
3.2.1 Polynucleotide synthesis
Two years after the publication by Crick and Watson, the research group of Alexander Todd reported the first
synthesis of a dinucleotide (dithymidine). Similar to peptide synthesis protecting groups are an important
factor in polynucleotide synthesis. Todd protected not only the free OH-groups (acetyl protected), but also
the internucleotide linkage (benzyl protected). This approach to oligonucleotide synthesis became known as
the phosphotriester approach.
Todd J. Chem. Soc. 1955, 2632
In the next 20 years, many different approaches were published. Khorana described a more convenient (but
also less selective) approach in which the internucleotide linkage stayed unprotected during synthesis
(phosphodiester approach). In the late 1960s, Todd’s method was reinvestigated by Letsinger and Reese. In
their approach, the phosphate group was protected with a 2-cyanoethyl group.
Khorana JACS 1958, 80, 6212
Letsinger JACS 1969, 91, 3350
Reese Chem. Commun. 1968, 767
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Caruthers and Köster finally introduced an approach that is nowadays considered as the state of the art for
oligonucleotide synthesis. The advantage of their method is that they start from more reactive phosphor(III)
triesters (nucleoside phoshporamidite building blocks, commercially available). The method can be
performed on solid phase (control pore glass, CPG) and is fully automated.
Caruthers JACS 1981, 103, 3185
Köster Nucleic Acids Res. 1984, 12, 4539
3.2.2 Examples: Oligonucleotide-peptide conjugate synthesis
Oligonucleotide-peptide conugates have been studied as specific inhinitors of gene expression in cells. The
stepwise solid phase synthesis of the peptide and the oligonucleotide sequence on a single solid support is
the most direct route to such conjugates. Gait and co-workers published a combined Fmoc SPPS/
oligonucleotide approach on a controlled pore glass support.
Gait OL 2002, 4, 3259
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4
Polyketide and fatty acid synthesis
4.1
Biosynthesis
Fatty acids are common precursors for many secondary metabolites such as prostaglandins, leukotrienes,
pheromones, and so on. The main building blocks of fatty is acetate in the form of acetyl-SCoenzyme A,
which is converted into malonyl-SCoenzyme A via carboxylation reaction. They are assembled by repeated
head-to-tail linkage, until the required length is reached.
Weissman PNAS 2001, 18, 380
Polyketide metabolites are classified as aromatic and non-aromatic including macrolides, polyenes,
polyethers. They are built via iterative polyketone from acetate, propionate building blocks, followed by
reduction and/or cyclisation and/or aromatization.
Weissman PNAS 2001, 18, 380
Rawlings Nat. Prod. Rep. 1997, 523
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4.2
Polypropionate synthesis
The synthetic mimicking of polyketide synthase controlled chain growth has fascinated many research
groups. The iterative construction of polypropionates is one example for a successful implementation of this
mimicking strategy.
Staunton Chem. Rev. 1997, 97, 2611
In the mid 1990s Paterson introduced a system to generate polypropionates via boron-aldol chemistry using
enantiopure (R)- and (S)-1-(benzyloxy)-2-methylpentan-3-one (4) as building blocks.
Paterson JACS 1994, 116, 11287
Paterson Tetrahedron Lett. 1997, 38, 7441
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Paterson later attached the aldehyde starter unit to a polystyrene support. By incorporation of syn- and antireduction strategies for the intermediate ketones, an efficient synthesis of polyketide libraries was accessed.
Paterson ACIE 2000, 39, 3315
Another approach was introduced by Panek. He used iterative crotylation sequences with crotylsilanes to
obtain well-defined homoallylic ethers.
Panek JOC 1993, 58,1003
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Panek JACS 1997, 119,12022
Panek OL 2005, 7, 4435
Prieto used epoxidation/propynylalanation/Lindlar reduction sequences to construct all-anti polypropionates.
Prieto JOC 2009, 74, 2447
4.3
Polydeoxypropionate synthesis
Polydeoxypropionates are an important class of polyketides and consist of polymethyl alkyl chains. In nature
they are constructed by complete reduction of the intermediate propionate.
Khosla Chem. Rev. 1997, 97, 2577
Feringa, Chem. Comm. 2010, 46, 2535
11
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Many synthetic strategies have been developed for the polydeoxypropionate pattern. These strategies rely
on the selective introduction of methyl substituent in an iterative fashion and can be divided into non-catalytic
and cataylic methodologies. The first iterative polydeoxypropionate-synthesis was reported by Oppolzer via
1,4-additions of enantiopure methyl-branched organocuprates to chiral unsaturated camphor derived esters.
Years later D.R. Williams used oxazolidinones derived esters as a chiral auxiliary for the same reaction.
Oppolzer Tetrahedron Lett. 1986, 39, 4713
Williams JOC 2004, 69, 5374
Another strategy was based on the well-known chiral enolate alkylation. Different research groups introduced
several chiral auxiliaries for this approach (Evans, Masamune, Myers, Enders).
Evans JACS 1990, 112, 5290
Masamune ACIE 1995, 34, 793
Myers Synlett 1997, 457
Enders Tetrahedron Lett. 1998, 39, 7823
Myers Synlett 1997, 457
12
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Negishi used his zirconium-catalyzed asymmetric carboalumination (ZACA) chemistry for the construction of
deoxypropionates. Despite the elegance of the ZACA protocol, the stereoselectivities are not excellent and
purification of diastereomers is necessary after each step leading to significant loss of material.
Negishi PNAS 2004, 101, 5782; JACS 2006, 128, 2770
In 2005 Feringa and co-workers reported the iterative synthesis of polydeoxypropionates based on their
enantioselective copper-catalyzed 1,4-addition of MeMgBr to unsaturated thioesters.
Feringa JACS 2005, 127, 9966
Two years Loh showed later that also unsaturated esters could be used as building blocks. The moderate
yield of the reduction/olefination step can be explained by over-reduction of the esters.
Loh JACS 2007, 129, 276
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4.4
Polyol synthesis
Polyols are the last polyketide-family discussed in this course. Rychnovsky’s seminal work on the synthesis
of polyols is a landmark in this area. Rychnovsky used a combined iterative/convergent strategy based on
enantiomerically enriched chloro nitriles. The possibility of orthogonal nucleophilic (alpha-deprotonation) or
electrophilic activation (conversion to iodide) of these acetonides leads to a highly efficient assembly of
polyol chains.
Rychnovski JOC 1992, 57, 1559
Rychnovski Chem. Rev. 1995, 95, 2001
Enders used a similar strategy than Rychnovsky for the synthesis of anti-polyols. Sequential alkylation of
SAMP hydrazone obtained after deoxygenation and iodination a virtually enantio- and diastereopure building
block.
Enders Tetrahedron Lett. 1999, 40, 4169
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Kishi published an iterative synthesis of polyols via Cr-mediated catalytic asymmetric allylation of aldehydes.
The obtained olefin can be converted in one-pot (dehydroxylation/oxidative cleavage) into a new aldehyde
function for further iterations.
Kishi OL 2008, 10, 3077
5
Carbohydrate synthesis
5.1
Biosynthesis
- Carbohydrates (saccharides) contain four chemical groups: monosaccharides, disaccharides,
oligosaccharide and polysaccharides. They plays important roles in living things (enegy storage,
components of coenzymes, genetic molecules, immune system, …)
- Monosaccharides are the smallest carbohydrates, which cannot be further metabolized. Disaccharides are
formed via the condensation of two monosaccharides. Oligo- and polysaccharides are composed longer
chain of monosaccharides linked by glycosidic bond.
- In contrast to the biosynthesis of polypeptides, which depends on genetic codes, the structures of oligo-,
polysaccharides are determined by the action of enzymes.
Lindhorst “Essentials of Carbohydrate Chemistry and Biochemistry” 2007, 229
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5.2
Glycosylation (= Glycosidation)
Glycosidic bond formation (glycosylation) is achieved by a displacement of a leaving group at the anomeric
position of one sugar (glycosyl donor) with the free hydroxyl group of another (glycosyl acceptor). Such a
transformation may be iterated to build up larger oligosaccharides. In iterative oligosaccharide synthesis, the
glycosylation is the coupling step.
Davis and Fairbanks, “Carbohydrate Chemistry”, Oxford University Press, 2002
Lindhorst, “Essentials of Carbohydrate Chemistry and Biochemistry”, 3rd ed., Wiley-VCH, 2007
Stereoselective glycosylation with neighboring group participation
Demchenko, “Handbook of chemical glycosylation: Advances in Stereoselectivity and
Therapeutic Relevance”, Wiley-VCH, 2010
5.3
Protecting groups
The selection of appropriate protecting groups is one of the most important steps in oligosaccharide
synthesis. The required properties of an ideal protecting group are as follows:
(1) readily available reagents are necessary for its introduction and removal
(2) it should be readily characterized; its introduction is not accompanied by the formation of a new
asymmetric center, but if this cannot be avoided, only one stereoisomer must be present
(3) it should be stable in most of the chemical transformations
(4) it should be compatible with the work-up conditions.
Common classes of protecting groups in carbohydrate chemistry:
(1) ethers: benzyl, substituted benzyl, allyl, silyl ethers (TMS, TES, TIPS, …) …
(2) esters: acetate, benzoate, chloroacetate, pivalate (Piv), levulinate (Lev), …
(3) acetals: benzylidene, isopropylidene, butane diacetal, …
General order of reactivity of hydroxyl groups in carbohydrate chemistry:
Lipták, Borbás & Bajza Ch-1.06 in “Comprehensive Glycoscience”, Elsevier, Oxford, 2007, pp 203–259
16
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The protecting groups in the oligosaccharide synthesis are not only used to block selectively interfering
functions but influence the reactivity and stereoselectivity in the glycosylation steps as well.
Kim Top. Curr. Chem. 2011, 301, 109
Cirth Top. Curr. Chem. 2011, 301, 141
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Switching the protecting groups among R1, R2, and R3 resulted in different stereoselectivities.
Kim JACS 2009, 131, 17705
5.4
The challenges of oligosaccharide synthesis
Carbohydrates are unique in the complexity of their structures. In contrast to the other two major classes of
biologically important biopolymers, proteins and nucleic acids, oligo- and polysaccharides are built up of
monomers that have more than two functional groups participating in an oligomerization reaction.
(1) Need to be protected. In a sugar residue one or more of several different hydroxyl groups can be
glycosylated, thus allowing also the formation of branched structures.
(2) Stereoselectivity. The formation of glycosidic linkage can result in a new stereogenic center and lead to
one of two different stereoisomers, the - or the -glycoside.
(3) Not a linear assembly. Many more constitutional stereoisomers can be constructed from
monosaccharides than from amino acids or nucleotides from which only linear oligomers can be designed.
Seeberger ACS Chem. Biol. 2007, 2, 685; Chem. Soc. Rev. 2008, 37, 19
Lindhorst, “Essentials of Carbohydrate Chemistry and Biochemistry”, 3rd ed., Wiley-VCH, 2007
Laine Glycobiology 1994, 4, 759
5.5
Armed/disarmed principle
For classic oligosaccharide synthesis, it always takes many steps for protecting/leaving group manipulations
and for glycosylation sequences. The previous attempts to eliminate these problems emerged in the mid1980s and 1990s, which resulted in the development of some revolutionary approaches. One strategy in
expeditious oligosaccharide synthesis arose from the discovery of the so-called arm/disarmed approach by
B. Fraser-Reid and co-workers (1988). This approach allows for direct chemoselective coupling between
an activated (armed) glycosyl donor and a deactivated (disarmed) glycosyl acceptor, and the resulting
disaccharide can then be used directly in subsequent glycosylation.
Fraser-Reid JACS 1988, 110, 2662; Top. Curr. Chem. 2011, 301, 1
Demchenko Top. Curr. Chem. 2011, 301, 189
(1) Electronic effects:
In the following example, oxidative hydrolysis (NBS, H2O) of n-pentenyl glycosides required minutes when
the C-2 protecting group was an ether, but hours when it was an ester. The origin of arm-disarmed principle
came form this result and the inspiration of Paulsen’s 1982 review which included the information that
“benzyl compounds are always more reactive than the acetylated or benzoylated derivatives.”
17
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Fraser-Reid JACS 1988, 110, 2662
The selectivity in the reaction is due to the stronger electron withdrawing power of the esters compared to
the ethers. A stronger electron withdrawing substituent leads to a greater destabilization of the
oxocarbenium ion. This slows this reaction pathway, and allows for disaccharide formation to occur with the
benzylated sugar. Other effective electron withdrawing groups that have shown selectivity are halogens and
azido groups, while deoxygenation has been proven an effective tool in “arming” sugars.
Wong JACS 1999, 121, 734
The following is the first example of armed/disarmed saccharide assembly. (IDCP = iodonium dicollidine
perchlorate. IDCP is a mild promoter)
Fraser-Reid JACS 1988, 110, 5583; the application in one-pot trisaccharide synthesis: J. Org. Chem. 1990, 55, 6068
(2) Torsional effects (conformational effects):
Cyclic protecting groups will “lock” the sugars into a rigid chair conformation and disfavor the formation of flat
oxocarbenium ion intermediate. This change in configuration is a high-energy transformation and leads to
the sugar being “disarmed”.
Fraser-Reid JACS 1991, 113, 1434; Top. Curr. Chem. 2011, 301, 1
An important influence: One of two major developments of carbohydrate chemistry, programmable one-pot
glycosylation, is an extensive advancement of the armed/disarmed principle. (For iterative oligosaccharide
synthesis, we will focus on the other one: solid-phase oligosaccharide synthesis.)
Wong JACS 1999, 121, 734; Chem. Rev. 2000, 100, 4465
Several examples:
(1) cis,cis-trisaccharide synthesis by armed/disarmed approach (Reminder: the excellent diastereoselectivity
in this example was NOT the outcome of armed/disarmed principle. In carbohydrate chemistry, the leaving
groups, promoters, or even solvents play important roles in the selectivity of the reactions.)
18
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van Boom Tetrahedron Lett. 1990, 31, 275
(2) cis,trans-trisaccharide synthesis by armed/disarmed approach
Demchenko ACIE 2005, 44, 7123
(3) trans,trans-trisaccharide synthesis by armed/disarmed approach
Demchenko ACIE 2005, 44, 7123
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5.6
Examples of iterative oligosaccharide synthesis
Iterative oligosaccharide synthesis by high reactive -bromoglycosides from selenoglyosides
Yamago & Yoshida Org. Lett. 2001, 3, 3867
Iterative synthesis of linear oligoglucosamines: two kinds of acceptors (1 & 2) were treated into different
steps to afford eight tetrasaccharide isomers.
Yamago ACIE 2004, 43, 2145
Iterative synthesis of -(14)-linked polysaccharides based on 3-O-methyl-D-mannose unit:
3-O-methyl-D-mannose-containing polysaccharides (MMPs) and 6-O-methyl-D-glucose-containing
lipopolysaccharides (MGLPs)/6-O-methyl-d-glucose-containing polysaccharides (MGPs), have
profound effects on the fatty acid biosynthesis.The synthetic MMPs (sMMPs) were made for mechanism
study in Kishi’s group. (Here we show the 2 nd generation of sMMPs synthesis.)
Kishi J. Org. Chem. 2007, 72, 1931 (1st generation); Org. Lett. 2007, 9, 3323 (2nd generation)
For sMGPs synthesis: J. Org. Chem. 2007, 72, 1941 (1st generation); Org. Lett. 2007, 9, 3327 (2nd generation)
For biosynthesis mechanism study: ChemBioChem 2007, 8, 1775
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Solid-phase oligosaccharide synthesis (SPOS)
The advantages of SPOS:
(1) only one chromatography step is needed in most cases at the end of the reaction
(2) unwanted reagents and side products can be removed simply by washing and filtering, and so a large
amount of the glycosyl donor or acceptor can be applied to ensure the high production yield
Key issues in SPOS:
(1) selection of the polymer support, (2) linker design, (3) choice of the glycosyl donor or acceptor, (4)
selection of a protecting group pattern for protection, (5) monitoring of the reaction course, and (6) product
cleavage from the resin and product characterization.
Seeberger Chem. Soc. Rev. 2008, 37, 19
Schmidt Frontiers in Modern Carbohydrate Chemistry. March 13, 2007, 209 (Chapter 3)
Wong ACIE DOI: 10.1002/anie.201100125
Selective examples:
Acceptor-bound approach: the glycosyl acceptor was immobilized on the solid phase. In 1998, Nicolaou
build up a dodecasaccharide via this approach.
Nicolaou JACS 1997, 119, 449; ACIE 1998, 37, 1559
Donor-bound approach:
In Danishefsky’s 1993 report, this SPOS was performed by repeated glycosylations with a growing solidbased donor and a solution-based acceptor (itself a glycal). Excess acceptor and promoter were removed by
rinsing after each coupling, and the desired oligosaccharides were then easily obtained from the polymer by
the addition of TBAF. By this method, glycosidations are stereospecific and interior deletions were avoided.
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Danishefsky Scince 1993, 260, 1307; JACS 1995, 117, 5712
Now, it is widely accepted that the acceptor-bound approach is more advantageous. An excess of the
reactive donor can drive the reaction to completion. More importantly, side reactions typically occur by
decomposition of the reactive species. If the donor is the limiting reagent as for the donor-bound
approach, any unproductive side reaction will result in a direct reduction in overall yield.
Seeberger Chem. Soc. Rev. 2008, 37, 19
Automated SPOS
An ideal automated SPOS:
(1) A set of monosaccharide building blocks with suitable protective groups should be needed
(2) Coupling and deprotection conditions should be rapid, selective and quantitative
(3) Real-time monitoring of coupling efficiency is highly desirable
(4) Efficient cleavage of the linker at the end of the synthesis should render the oligosacharide either as the
free reducing terminus or in a form that allows for the creation of glycoconjugates
(5) Ready removal of all protective groups
(6) Purification and quality control of the final product
Synthetic strategy: acceptor-bound approach
Automated oligosaccharide synthesis relies on the attachment of the nucleophile to the solid support, the
acceptor-bound approach.
Application:
The automated oligosaccharide synthesis has been used to synthesize several important carbohydrates,
which include globo-H hexasaccharide, the core pentasaccharide of N-linked glycans, -mannoside,
oligomannosides, oligorhamnosides, the phytoalexin elicitor family of glucans, and the parasitic vaccine
candidates against malaria and leishmaniasis.
Seeberger Chem. Soc. Rev. 2008, 37, 19
Wong ACIE DOI: 10.1002/anie.201100125
The general applicability of automated SPOS is nicely demonstrated by the synthesis of a nonasaccharide of
Ley-Lex (KH-1) antigen derivative.
Seeberger ACIE 2004, 43, 602
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Seeberger and co-workers first introduced an automated oligosaccharide synthesizer, which was modified
from an original peptide synthesizer and optimized for automated SPOS.
Seeberger Science 2001, 291, 1523
Future challenges:
(1) Building blocks are used in excess
(2) Complete control over stereochemistry at each new anomeric carbon cannot be exercised
(3) Not every glycosidic linkage can presently be installed by automated synthesis
(4) Thioglycoside building blocks cannot be used
(5) Linker cleavage is slow
(6) Linker functionalization and protecting group removal require several steps
(7) The low temperature (below -20 oC) converted peptide synthesizer is not commercially available
Seeberger Carbohydr. Res. 2008, 343, 1889
6
Iterative cross-coupling reaction
6.1
Iterative cross-coupling reactions
Cross-coupling reaction is a reaction in which two fragments are coupled with the aid of catalyst. An ideal
cross-coupling reaction should happen in mild conditions, functional group tolerance, allows the assembly of
collection of building blocks pre-constructed with all required functional groups and correct stereochemical
relationship.
Amongst the cross-coupling reactions, metal-catalyzed cross-coupling reactions are the most popular ones.
(Nobel Prize in Chemistry 2010)
Common metal-catalyzed cross-coupling reactions:
Iterative cross coupling strategy has been used for a long time in the synthesis of organic polymers
(oligothiophene, oligo(-phenylene ethynylene)s, …). In those case, the required building blocks (monomers)
are easily activated or protected allow selective coupling (ex: halogenation of thiophene). Recently, the
synthesis of more challenging oligoarenes with benzene or its derivatives as monomers has been
developed.
6.2
-Conjugated oligomers - Oligothiophene synthesis
- -Conjugated oligomers (including oligoenes, oligoenynes, oligoenediynes, oligoynes, oligostyrenes,
oligothiophene,…) are widely used in material science for electronic and photonic applications. The most
elegant and efficient way to prepare them is iterative strategy.
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- In this lecture note, we will focus on the synthesis of oligothiophenes, which received the most careful
studies and applications in industry (transitors, diodes, electroluminescent devices). Amongst the methods
for thiophene preparation, iterative cross-coupling reactions (Kumada, Suzuki-Miyara, Stille) have been
widely used.
Diederich ACIE 1999, 38, 1350
Iterative oxidative cross-coupling. This method restricts to symmetrical oligothiophenes and thiophene-based
materials with no base-sensitive functional groups.
Lukevics 2003, 60, 663
Iterative Suzuki-Miyaura cross-coupling (solution / solid phase)
Suss-Fink et al. Heteroatom Chemistry 2004, 15, 121
Bauerle Chem. Comm. 2002, 1015
“Double coupling” oligothiophene synthesis.
Spivey et al. developed a new strategy for the synthesis of regioregular oligothiophene that allows for
double-coupling after each iteration to minimize deletion sequences.
Spivey Org. Lett. 2002, 4, 1899
6.3
Oligoarene synthesis
- Oligoarenes are oligomers of aromatic rings such as benzene and/or its derivatives through single bonds.
They are widely used as backbones in molecular electronics, self-assembling molecules, bioactive
compounds, catalysts, …
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The most reliable and efficient method to synthesize multifunctionalized oligoarenes is the repetitive addition
of each building block - monomer - via cross-coupling reaction: iterative cross-coupling (esp. Suzuki-Miyaura
cross-coupling reaction). In this type of iterative cross-coupling approach, building blocks having all the
required functional groups, with required stereochemistry are connected using stereospecific, chemospecific
cross-coupling reactions.
Manabe Chem. Comm. 2008, 3829
6.3.1 Protection of electrophiles
Methoxyphenylboronic acids were used precursors of monomers in the synthesis of oligoarene by Hamilton
et al. After the Suzuki-Miyaura coupling of boronic acid and aryl triflate, methoxy group was converted into
triflate in two steps (activation step) ready for the next coupling.
Hamilton ACIE 2002, 41, 278
Hydroxyphenylboronic acids or pinacol boronates as precursor by Manabe. Hydroxyl group was converted to
triflate prior to the following cross-coupling.
Manabe Chem. Comm. 2006, 2589
25
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6.3.2 Borylation of boron-free compounds
Borylation the precursor is another activation method to obtain boronic acid for the next cross-coupling step
to elongate the chain. Limitation of those methods is harsh conditions of converting to boronic acid.
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Directed ortho-borylation
Directing groups may be –OMOM, –OCONEt2, –CONEt2
Snieckus Tet Lett 1987, 28, 5097
Br-Li exchange followed by borylation
Simpkins Synthesis 1996, 614
6.3.3 Protection of boron
- It is hypothesized that transmetallation between boronic acid and Pd (II) required a vacant and Lewis acidic
boron p orbital (sp2 boron center). For example, pinacol boronic esters (complexation of boron and electrondonating ligand) are less reactive than corresponding boronic acids.
- Suginome and Burke have independently developed two different protecting groups for boronyl groups
(based on different concepts – see in the scheme). These studies are great breakthroughs in iterative
Suzuki-Miyaura cross-coupling since these masked boronyl groups can be easily formed, stable and
activated under mild and orthogonal conditions. This fact overcomes the hard conditions in protecting
electrophiles or borylation strategies.
26
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Interesting reviews: Manabe Chem. Com. 2008, 3829
Glorius ACIE 2009, 48, 5240
Burke AldichimicaActa 2009, 42, 17
Lowering Lewis acidity of Boron
This strategy not only applied for the synthesis of oligoarenes, but oligo(phenylenevinylene)s, phenyl
denrimers as well.
Suginome JACS 2007, 129, 758; Org. Lett. 2009, 11, 1899
sp3 rehybridized Boron center (MIDA boronate)
As dicussed previously, the complexation of boron and trivalent N-methyliminodiacetic acid (MIDA) ligand
deactivates the boron center by rehybridizing B sp2 to B sp3. These building blocks (MIDA boronates) are
easily to prepare, bench-stable, soluble in many organic solvents, compatible with silica gel chromatography,
and orthogonally cleaved under mild aqueous basic conditions (1N NaOH). More than 50 of them including
aryl, heteroaryl, alkenyl, alkynyl MIDA are now commercially available.
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Burke JACS 2007, 129, 6716; ACIE 2011, 50, 7862
See also the synthesis of Polyene Natural Products via iterative cross-coupling: Burke JACS 2008, 130, 466
7
Dendrimers
Dendritic molecules have drawn much attention in the supramolecular chemistry, theoretical, physical,
polymer and inorganic chemistry due to their material properties. A great number of studies and examples on
these molecules have been published. In general, there are two major iterative strategies for the synthesis of
uniform dendritic molecules:
- Divergent-iterative pathway
- Convergent-iterative pathway
Vögtle Top. Cur. Chem. 1998, 197, 1
8
Other examples
8.1
Oligo-oxazole synthesis
Oligo-oxazole motifs, especially the C2-C4’ linked moieties, are found in various natural products. For the
preparation of these successive C2-C4’ linked oligooxazoles, a number of iterative methods have been
developed.
28
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8.2
Iterative Diels-Alder synthesis
Belt-like, ribbon-shaped structures of polyacenes and their derivatives are of the interest for the studies of
orbital interactions, host/guest phenomena. One of the strategies to prepare those compounds is iterative
Diels-Alder reactions.
Iterative Diels-Alders reactions are also used in preparation of benz[α]anthracene antibiotics:
1,4-difluoro-2,5-dimethoxybenzene as precursor for iterative double benzyne-furan Diels-Alder reactions.
Barrett JOC 2005, 70, 3525
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