Wyniki wyszukiwania - BazTech

1

Reakcja Mitsunobu : mechanizm i zastosowanie

Kitkowska J. D., Tabaczyńska Ż. A., Dramiński M.

Wiadomości Chemiczne

|

2013

|

[Z] 67, 9-10

843--876

EN

The Mitsunobu reaction has been known since 1967, but the research on its modifications as well as on the introduction of new reagents, productivity, improvement and methods of post-reaction mixture separation is still being conducted. The original reaction was used to obtain esters by condensation of carboxylic acids and alcohols using triphenylphosphine and DEAD mixture. This reaction allows formation of s not only carbon-oxygen bond, but also carbon-carbon, carbon-nitrogen, and carbon-sulphur to be synthesized. The Mitsunobu reaction is widely applied in organic synthesis as a way of inversion of configuration of secondary alcohols or of aryl ethers synthesis. Numerous studies bring the accounts of using this reaction for the synthesis of steroids, carbohydrates, nucleosides, as well as alkaloids and other heterocyclic compounds containing nitrogen. The popularity of this reaction lies in its stereoselectivity and compatibility with a wide range of functional groups as well as in its moderate requirements considering reaction conditions. However, an isolation of a desirable product from the used up or surplus reagents still causes a lot of difficulties.

2

β-laktony pochodnych seryny jako prekursory aminokwasów wielofunkcyjnych

Olma A., Kudaj A.

Wiadomości Chemiczne

|

2010

|

[Z] 64, 9-10

831-857

EN

Optically active unnatural amino acids play important roles in bioorganic and medicinal chemistry [1]. Thus, development of novel methods for the synthesis of these amino acids is of great interest for organic chemists. Incorporation of these building blocks often results in peptidomimetics with limited conformational flexibility, enhanced enzymatic stability, improved pharmacodynamics and bioavailability. This review summarizes the utilization of β-lactones of serine and of α-alkylserines in the enantioselective synthesis of β-substituted alanines. N-Protected β-hydroxy-α-amino acids can be cyclized under modified Mitsunobu conditions to β-lactones [2–19]. Serine and threonine β-lactones can be also obtained by carboxyl group activation using coupling reagents (DIC, TBTU, HBTU, BOP, PyBOP, HBTU) [16, 21–27]. Readily accessible β-lactone ring opening with various nucleophiles provides many unnatural amino acids and other chiral building blocks. In the first part, the synthesis of N-protected β-hydroxyamino acid β-lactones and the ring opening mechanism are discussed [30, 31]. The second part of this review describes the ring opening with various nucleophiles, including halogens, thiols, selenes and tellures, nitrogen, phosphorus and carbon nucleophiles. Reactions of N-protected β-hydroxyamino acid and α-alkylserines β-lactones with halogen nucleophiles (HCl, HBr, LiCl, and MgX_2) in all described cases yield α-halogenomethyl derivatives [2, 20, 25, 32, 33]. α-Halogenomethyl-α-amino acids are potential enzyme-activated irreversible inhibitors of parent amino acid decarboxylases. Only a few synthetic strategies directed towards the synthesis of the selected α-halogenomethylamino acids have been described. The difficulty associated with the synthesis of these molecules lies in the presence of a halogen atom on the carbon atom vicinal to quaternary center bearing amine and carboxylic acid functionalities (like the neopenthyl position). Sulphur, selenium and tellurium nucleophiles were used to obtain S-substituted cysteines, α-alkylcysteines and lanthionine derivatives and their seleno and telluro analogues [2, 28, 32, 33, 44, 45, 49–54]. The use of nitrogen nucleophiles leads to β-amino-, β-cyano- and β-azidoalanines [2, 11, 13–15, 32, 33, 55–71]. Properties of the nucleofile and of β-lactone determine regioselectivity of ring opening, giving β-aminoalanines or amides. The use of sodium azide as the nucleophile led to the formation of β-azidoalanine and β-azido-α-alkylalanines, useful building blocks in peptide synthesis and precursors of α, β-diamino acids. Among nitrogen nucleophiles the cyclic secondary amine (pyrolidine, morpholine), aromatic amines and heterobases were used to synthesize β-aminoalanine derivatives. The β-lactone ring openings were carried out with phosphorus [10, 18, 72, 73] and carbon nucleophiles [5, 74–76]. Serine, threonine and α-alkylserines β-lactones are widely used intermediates for the synthesis of new optically pure unnatural, multifunctional amino acids, which are difficult to obtain in other ways.

3

Modyfikowane i alternatywne reagenty reakcji Mitsunobu

Kołodziejczyk A.S.

Wiadomości Chemiczne

|

2010

|

[Z] 64, 11-12

1073-1097

EN

The Mitsunobu reaction provides an extremely useful and versatile synthetic route for a large array of products involving formation of a new C-O, C-N, C-S, C-X, or C-C bond. The reaction is a dehydrative coupling of an alcohol with an acid/pronucleophile using a combination of an oxidizing azo reagent and a reducing phosphine reagent -equation (1). The reaction is very popular due to its stereoselectivity and compatibility with a wide range of functional groups. However, the use of this method is complicated by the resulting complex reaction mixtures containing a product, triphenylphosphine oxide and the reduced azodicarboxylate, as well as unreacted starting material. Due to omnipresence of the Mitsunobu reaction, it was a subject of numerous reviews [1-12]. The mechanism and the stereochemical result of the reaction are still thoroughly studied [22-38] and the current, generally accepted mechanism is outlined in Scheme 1. This article provides an overview of the separation-friendly strategies introduced to facilitate product isolation in the Mitsunobu reaction and its modified and alternative mediators. As two comprehensive reviews devoted to modified Mitsunobu reagents and separation techniques facilitating isolation of the condensation product appeared fairly recently [7, 8], this work concentrates on examples of isolation-friendly strategies and studies subsequent to mentioned reviews. Separation facilitating strategies are based on tagging one of Mitsunobu reagents or substrates with a "separation tag" (phase tag, affinity tag), which controls the behaviour of the component and allows to separate the tagged reaction component from untagged ones. There are four main separation techniques used in the Mitsunobu reaction: polymerassisted phase-switching or solid phase immobilization (2.1.1.), acidic/basic aqueous work-up (2.1.2.), fluorous approach (2.1.3.), and post-reaction sequestration. Both phosphine and azodicarboxylate can be attached to insoluble polymer and the derived side-products (phosphine oxide or hydrazodicarboxylate) can be removed by filtration at the end of the reaction. Fluorous tagging makes possible the separation of a fluorous compound from nonfluorous ones either by partitioning between a fluorous and an organic liquid or by fluorous solid-phase extraction (FSPE) - Scheme 6. A fluorous-tagged acid was also applied to achieve inversion of an alcohol configuration (Scheme 8). Another separation-facilitating strategy uses polymerizable Mitsunobu reagents and post-reaction sequestration, e.g. by ring opening metathesis polymerization (ROMP), either of a condensation product (Scheme 9), or side products (impurity anihilation). The scope of the Mitsunobu reaction was greatly widened by introduction of alternative Mitsunobu reagents by the Tsunoda-Itô group [69-79]. Some of these reagents (1-4, Scheme 12) mediate C-alkylation reactions of very weak acids (pK_a > 23) [77, 78]. Several other modified Mitsunobu reagents are also described.

4

Alternatywne mediatory reakcji Mitsunobu

Falkiewicz B., Wiśniewski K., Kołodziejczyk A.S.

Wiadomości Chemiczne

|

2001

|

[Z] 55, 9-10

849-858

EN

The Mitsunobu reaction is a versatile method for the alkylation of various Bronsted-Lowry acids (HA) by alcohols, proceeding in neutral media in a presence of the redox system which traditionally consists of diethyl azodicarboxylate and triphenylphosphine. The key step of the process proceeds according to the SN2 mechanism and results in one of the most useful attributes of the reaction, namely complete configurational inversion at the carbinol carbon. The reaction, however, has a serious limitation - the acidic component has to have pKa smaller than 13 for the reaction to proceed smoothly. Moreover, the classical methodology of the reaction suffers from low yields when applied to secondary alcohols. In recent years, in order to overcome these drawbacks and expand the versatility of the original combination of the Mitsunobu mediators, significant progress in the reaction methodology has been made, mainly due to the work of Tsunoda and Itô. Two types of new mediators have been developed to replace the azodicarboxylate-TPP system. The first one is an N,N,N',N'-tetrasubstituted azodicarboxamide - tributyl phosphine system. All azodicarboxamide derivatives were found to be more efficient than traditional DEAD in the Mitsunobu reaction, especially for less acidic HX. N,N,N',N'-Tetramethylazodicarboxamide, TMAD, gives the best overall results among acyclic amides, whereas 4,7-dimethyl-3,5,7-hexahydro-1,2,4,7-tetraazocin-3,8-dion, DHTD, in combination with TBP was found to be unique in mediating the formation of the C-C bond with sec-alcohols at room temperature. The other type of new mediators in the Mitsunobu reaction, structurally based on betaine, is cyanomethylenetrialkylphosphorane. The phosphorane reagents are generally less active at room temperature, but in higher temperatures they are, esp. CMMP, better than DHTD-TBP and afford satisfactory alkylation of secondary alcohols. Furthermore, the phosphorane reagents mediate the reaction of acids of pKa up to 23.5 [33]. Comparative studies of the C-alkylation revealed the general reactivity of new mediators as TMAD-TBP ( DHTD-TBP ( CMBP ( CMMP.

5

Zastosowania reakcji Mitsunobu w chemii aminokwasów

Wiśniewski Kazimierz, Kołodziejczyk Aleksandra S., Falkiewicz Bogdan

Wiadomości Chemiczne

|

1998

|

[Z] 52, 3-4

243--267

EN

The Mitsunobu reaction has been knowm since the late sixties. It is mediated by the redox system : triaryl - or trialkylphosphine/dialkyl azodicarboxylate and brings about the nucleophilic substitution of an alcoholic hydroxyl group by the conjugate base of an acidic reactant, with inversion of configuration at the alkohol carbon. The Mitsunobu reaction is widely used in organic chemistry and its mechanism (Scheme 1) has been intensively studied (for review - see [2-5]). This article deals with the application of the reaction in the chemistry of amino acids. The reaction was proposed as an effective method of a-amino acid synthesis using hydroxy acids as substrates. As the amino group synthons phtalimide [10, 11], (Scheme 2), hydrazoic acid [14], (Scheme 5) or t-butyl-2(trimethylsilil)ethylsulphonylcarbamate [18], (Scheme 7) were used. The procedure using HN3 was profoundly improved by the introduction of a stable bis-pyridine complex of zinc oxide [16]. The use of phtalimide as an amino group precursor in Mitsunobu-type reaction was successfully applied to the synthesis of 2-2H-labelled chiral glycine [13], (Scheme 4). In the model studies on the synthesis of 15N-labelled N-protected chiral amino acids Degerbeck et al. [17] found that the yield of the Mitsunobu conversion (Scheme 6) depends on the acidity of the NH function in the imidocarbonate or sulphonylcarbamate used. The Mitsunobu reaction has also been applied to the synthesis of many unnatural or modified amino acids such as protected 2,3-diamino butyric acid [19], 3- or 4- mercaptoproline derivatives [20, 21], (Scheme 8), N5-acetyl-N5-hydroxy-L-ornitine [22], (Scheme 9) and a-N-hydroxyamino acids [23], (Scheme 10). Wojciechowska et aal[24] have reported the preparation of dehydroamino acids from protected serine and threonine derivatives under the intramolecular Mitsunobu dehydration condition (Scheme 11). A general approach to the preparation of N-monoalkylated amino acids based on the Mitsunobu reaction has been developed [3-] using N-tosylamino acid esters as acidic components of the reaction (Scheme 15). Since the removal of tosyl group is difficult, a modification of the N-alkylation procedure has recently been devised [32, 33]. The Mitsunobu reaction is also an excellent procedure for transforming hydroxy acids or hydroxy amino acids into esters whose subsequent hydrolysis leads to a stereoisomer of the initial compound with the inverted configuration at the carbinol centre and was very often used in this way [37, 38], (Schemes 8 and 17). The Mitsunobu reaction provides also an interesting method of esterification in which an alcohol, not a carboxylic component, is activated. It was used to the synthesis of diphenylmethyl esters of N-trityl amino acids [43], to the attachment of a first amino acid to the polymer support [44] or to active ester synthesis [45], (Scheme 18). The applications of the Mitsunobu reaction include also the preparation of amny cyclic derivatives of amino acids such as B-lactams [51], (Scheme 20), aziridines [49, 54], (Schemes 19, 21) or B-lactons [60]. The last cyclic derivatives are valuable intermediates for the synthesis of B-substituted alanines (Scheme 22). B-Lactonization proceeds easily in case of serine derivatives whereas in threonine derivatives B-elimination is the dominant reaction [61], (Scheme 23). The review deals also with the application of the title reaction to the synthesis of peptide (polyamide) nucleic acids (PNA) [31, 39, 40, 68-70].