Editing Solid-phase synthesis

{{Short description|Method of synthesizing complex molecules}}
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In [[chemistry]], '''solid-phase synthesis''' is a method in which [[molecule]]s are [[Covalent bond|covalently bound]] on a [[solid]] support material and synthesised step-by-step in a single [[reaction vessel]] utilising selective [[protecting group]] chemistry. Benefits compared with normal [[Chemical synthesis|synthesis]] in a [[liquid state]] include:

* High efficiency and throughput
* Increased simplicity and speed

The reaction can be driven to completion and high [[Yield (chemistry)|yields]] through the use of excess [[reagent]]. In this method, building blocks are protected at all reactive [[functional group]]s. The order of functional group reactions can be controlled by the order of deprotection. This method is used for the synthesis of [[peptides]],<ref>{{Cite journal|last=Merrifield|first=Bruce Arthur|date=1963|title=Solid Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide|journal=J. Am. Chem. Soc.|volume=85 |issue=14|pages=2149–2154|doi=10.1021/ja00897a025|bibcode=1963JAChS..85.2149M }}</ref><ref>{{Cite journal|last=Palomo|first=Jose M.|date=2014|title=Solid-phase peptide synthesis: an overview focused on the preparation of biologically relevant peptides|journal=RSC Adv.|language=en|volume=4|issue=62|pages=32658–32672|doi=10.1039/c4ra02458c|bibcode=2014RSCAd...432658P |issn=2046-2069|url=https://digital.csic.es/bitstream/10261/187255/1/Solid-phase_Palomo_Publisher2014.pdf|hdl=10261/187255|hdl-access=free}}</ref> deoxyribonucleic acid ([[DNA]]), ribonucleic acid ([[RNA]]), and other molecules that need to be synthesised in a certain alignment.<ref>{{Cite journal|last1=Krchňák|first1=Viktor|last2=Holladay|first2=Mark W.|date=2002|title=Solid Phase Heterocyclic Chemistry|journal=Chemical Reviews|language=en|volume=102|issue=1|pages=61–92|doi=10.1021/cr010123h|pmid=11782129|issn=0009-2665}}</ref> More recently, this method has also been used in [[combinatorial chemistry]] and other synthetic applications. The process was originally developed in the 1950s and 1960s by [[Robert Bruce Merrifield]] in order to synthesise peptide chains,<ref>{{Cite journal|last=Merrifield|first=B.|date=1986-04-18|title=Solid phase synthesis|journal=Science|language=en|volume=232|issue=4748|pages=341–347|doi=10.1126/science.3961484|issn=0036-8075|pmid=3961484|bibcode=1986Sci...232..341M }}</ref> and which was the basis for his 1984 [[Nobel Prize in Chemistry]].<ref>{{Cite web|url=https://www.nobelprize.org/prizes/chemistry/1984/summary/|title=The Nobel Prize in Chemistry 1984 - NobelPrize.org|website=NobelPrize.org|language=en-US|access-date=2018-09-25}}</ref>

In the basic method of solid-phase synthesis, building blocks that have two functional groups are used. One of the functional groups of the building block is usually protected by a protective group. The starting material is a bead which binds to the building block. At first, this bead is added into the solution of the protected building block and stirred. After the reaction between the bead and the protected building block is completed, the solution is removed and the bead is washed. Then the protecting group is removed and the above steps are repeated. After all steps are finished, the synthesised compound is chemically cleaved from the bead.

If a compound containing more than two kinds of building blocks is synthesised, a step is added before the deprotection of the building block bound to the bead; a functional group which is on the bead and did not react with an added building block has to be protected by another protecting group which is not removed at the deprotective condition of the building block. Byproducts which lack the building block of this step only are prevented by this step. In addition, this step makes it easy to purify the synthesised  compound after cleavage from the bead.

==Solid-phase peptide synthesis (SPPS)==

Solid-phase synthesis is a common technique for [[peptide synthesis]]. Usually, peptides are synthesised from the [[carbonyl group]] side (C-terminus) to [[amino group]] side (N-terminus) of the [[amino acid]] chain in the SPPS method, although peptides are biologically synthesised in the opposite direction in cells. In peptide synthesis, an amino-protected amino acid is bound to a solid phase material or resin (most commonly, low cross-linked [[polystyrene]] beads), forming a [[covalent bond]] between the carbonyl group and the resin, most often an [[amido]] or an [[ester]] bond.<ref>{{Cite journal|last1=Guillier|first1=Fabrice|last2=Orain|first2=David|last3=Bradley|first3=Mark|date=2000|title=Linkers and Cleavage Strategies in Solid-Phase Organic Synthesis and Combinatorial Chemistry|journal=Chemical Reviews|language=en|volume=100|issue=6|pages=2091–2158|doi=10.1021/cr980040+|pmid=11749285|issn=0009-2665}}</ref> Then the amino group is deprotected and reacted with the carbonyl group of the next N-protected amino acid. The solid phase now bears a dipeptide. This cycle is repeated to form the desired peptide chain. After all reactions are complete, the synthesised peptide is cleaved from the bead.

The protecting groups for the amino groups mostly used in the peptide synthesis are 9-fluorenylmethyloxycarbonyl group ([[Fluorenylmethyloxycarbonyl protecting group|Fmoc]]) and t-butyloxycarbonyl ([[Tert-Butyloxycarbonyl protecting group|Boc]]). A number of amino acids bear functional groups in the side chain which must be protected specifically from reacting with the incoming N-protected amino acids. In contrast to Boc and Fmoc groups, these have to be stable over the course of peptide synthesis although they are also removed during the final deprotection of peptides.

==Solid-phase synthesis of DNA and RNA==
{{Main|Oligonucleotide synthesis}}
Relatively short fragments of [[DNA]], [[RNA]], and [[modified oligonucleotides]] are also synthesised  by the solid-phase method. Although [[oligonucleotides]] can be synthesised  in a flask, they are almost always synthesised  on solid phase using a DNA/RNA synthesizer. For a more comprehensive review, see [[oligonucleotide synthesis]]. The method of choice is generally phosphoramidite chemistry, developed in the 1980s.

== See also ==
* [[Combinatorial chemistry]]
* [[Noncovalent solid-phase organic synthesis]]

== References ==
<references/>

== Further reading ==
* Solid-Phase Combinatorial Chemistry, see [http://www.combichemistry.com/solid_phase_synthesis.html]
* N-(pyrimidin-2-yl)amino acid amides in drug research, see [http://www.arkat-usa.org/ARKIVOC/JOURNAL_CONTENT/manuscripts/2005/NZ-1364JP%20as%20published%20mainmanuscript.pdf Full article]

[[Category:Solid-phase synthesis| ]]
[[Category:Chemical synthesis]]
{{chemical synthesis}}