Mitsunobu esterification

The Mitsunobu reaction is usually used to introduce an ester with inversion of configuration. The use of this methodology on an anomeric hydroxyl was found to give only the /3-benzoate, whereas other methods gave mixtures of anomers. Improved yields are obtained in the Mitsunobu esterification when p-nitrobenzoic acid is used as the nucleophile/ Bis(dimethylamino) azodicarboxylate as an activating agent was... 

Furthermore, the apphcabihty in a Mitsunobu esterification reaction and a Diels-Alder reaction was proven (Scheme 10.13). The polymer-bound benzyl alcohol (70) was reacted with 4-acetamidophenol in the presence of the Mitsunobu reagent to give phenyl ether (71) in quantitative yield. It was released from the polymeric support in high yield. 

Since depsipeptides, in contrast to classical peptides, contain units constructed from amino and hydroxy acid residues, the various methods for their preparation are generally pathways involving the formation of ester bonds. The novel achievements in this area discussed (vide infra) are associated with further developments in the mixed anhydride technique, the application of effective catalysts in the carbodiimide procedure, and adaptation of the known Mitsunobu reaction to the depsipeptide case. A number of significant and efficient esterification procedures utilized for the preparation of depsipeptides are considered. 

Both aliphatic alcohols and phenols have been immobilized as esters of support-bound carboxylic acids. The esterification can be achieved by treatment of resin-bound acids with alcohols and a carbodiimide, under Mitsunobu conditions, or by acylation of alcohols with support-bound acyl halides (see Section 13.4). 

Support-bound, enantiomerically pure alcohols can be converted into phosphonates by Mitsunobu esterification, which results in complete inversion at the stereo-genic center. This strategy has been used to prepare peptidyl phosphonates on solid phase. These are interesting transition-state analogs with potential utility as peptidase inhibitors (Figure 11.3 [12,13]) or tyrosine phosphatase inhibitors [14]. Serine or threonine derivatives can be converted into phosphonates by direct phosphonylation with an activated monoalkyl phosphonate [15] or by treatment with phosphonamidites RP(OR)NR2 in the presence of tetrazole followed by oxidation [16]. 

Transesterification under strongly basic reaction conditions has been used to acy-late support-bound alcohols with alkyl esters (Entry 10, Table 13.12). For sensitive acids, the Mitsunobu reaction is a particularly mild method of esterification. This reaction gives high yields with support-bound primary aliphatic alcohols and proceeds under essentially neutral reaction conditions (Experimental Procedure 13.4). Mitsunobu esterification of PEG with /V-Fmoc amino acids has also been reported [172]. 

Standard solid-phase peptide synthesis requires the first (C-terminal) amino acid to be esterified with a polymeric alcohol. Partial racemization can occur during the esterification of N-protected amino acids with Wang resin or hydroxymethyl polystyrene [200,201]. /V-Fmoc amino acids are particularly problematic because the bases required to catalyze the acylation of alcohols can also lead to deprotection. A comparative study of various esterification methods for the attachment of Fmoc amino acids to Wang resin [202] showed that the highest loadings with minimal racemization can be achieved under Mitsunobu conditions or by activation with 2,6-dichloroben-zoyl chloride (Experimental Procedure 13.5). iV-Fmoc amino acid fluorides in the presence of DMAP also proved suitable for the racemization-free esterification of Wang resin (Entry 1, Table 13.13). The most extensive racemization was observed when DMF or THF was used as solvent, whereas little or no racemization occurred in toluene or DCM [203]. 

The successful synthesis of optically active 7 then led to the first synthesis of verrucarin A (8), a macrotrilactone with significant cytostatic activity. The synthesis involved esterification of the primary alcohol of verrucarol (the tricyclic fragment) with the acetate of 7 (DCC, 4-pyrrolinopyridine) and then with a protected derivative of (E, Z)-muconic acid. After deprotection (Bu4NF), lactonization was effected by the Mitsunobu procedure (7,405-406). 

Mitsunobureaction.1 Two intermediates have been isolated from the Mitsunobu esterification of carboxylic acids with phenols. One is the betaine 1, which has been generally assumed to be involved the other is the phosphorane 2.2... 

Carbonates,4 Alcohols can be converted into the carbonates, ROCOOR, by reaction with CO, in THF under conditions of Mitsunobu esterification. Isolated yields (five examples) are in the range 40-80%. 

When esterification is achieved under the Mitsunobu conditions (diethyl azodicarboxylate, Ph3P), only esters at positions 6 and 6 are produced, and isolation of the 6-monoester, which is formed faster is possible. Thus diesters can be efficiently prepared.97 99 In this type of reaction, when the carboxylic acid is... 

The O-alkylation of carboxylates is a useful alternative to the acid-catalyzed esterification of carboxylic acids with alcohols. Carboxylates are weak, hard nucleophiles which are alkylated quickly by carbocations and by highly reactive, carbocation-like electrophiles (e.g. trityl or some benzhydryl halides). Suitable procedures include treatment of carboxylic acids with alcohols under the conditions of the Mitsunobu reaction [122], or with diazoalkanes. With soft electrophiles, such as alkyl iodides, alkylation of carboxylic acid salts proceeds more slowly, but in polar aprotic solvents, such as DMF, or with non-coordinating cations acceptable rates can still be achieved. Alkylating agents with a high tendency to O-alkylate carboxylates include a-halo ketones [42], dimethyl sulfate [100,123], and benzyl halides (Scheme 6.31). 

There are two problems. Enolates of primary amides are not very practical as the NH protons are more acidic than the CH protons. The solution is to use the nitrile and hydrolyse it later to the amide. A more serious problem is that the Sn2 reaction we want to use to couple the two together will go with inversion and that will give the biologically inactive enantiomer of darifenacin. The solution is a double inversion. Protection of the amine by tosylation 67 is followed by tosylation of the alcohol with inversion using a Mitsunobu-style reaction. This unusual esterification goes reliably with inversion.20... 

Another alternative for incorporation of the first protected amino acid onto hydroxymethyl base resins without activation of the carboxy group is by a Mitsunobu reac-tion.f l The esterification of 4-hydroxymethylphenoxy-type resins by Fmoc-protected amino acids using this method was first reported by Sieber,P l who observed the presence of an unidentified hydrophobic impurity in the amino acids cleaved from the resin however, independent studies by the groups of Krchnak and Spatola l have shown that the esterification of 4-hydroxymethylphenoxy-type PSty and PEG-PS resins using this procedure proceeds rapidly with acceptable to good yields, with practically no racemization and without the presence of additional contaminants in the final product. On the other hand, this method did not provide satisfactory results for cellulose supports.P l... 

The following esterification is an example of the Mitsunobu reaction. PROBLEM 3.22 Notice that there is inversion of configuration at the asymmetric carbon bearing the alcohol group in the starting material. 

The reaction of an alcohol and a carboxylate anion with diethyl azodicarbox-ylate EtOOCN=NCOOEt and PhsP is called the Mitsunobu esterification reac-tion. This reaction can also be considered as an 8 2. Other Mitsunobu catalysts are available, " and a polymer-bound phosphine has been used. A renewable phosphine ligand has been developed. Note that other functional groups, including azides and thiocyanates can be generated from alcohols using Mitsunobu conditions. 

---