Mitsunobu reaction lactonization

Scheme 21 shows the synthesis of a dihydrofuran derivative 86. Synthesis of this compound was described by Nam et al. [68] utilizing a furanone compound 87 synthesized by Kim et al. [61] via a similar synthetic approach as described in Scheme 17. The lactone was reduced using lithium aluminum hydride to give the diol 88 and intramolecular etherification using the Mitsunobu reaction afforded the dihydrofuran 86 in moderate yield (47%).

In a process resembling the Mitsunobu reaction (Chapter 17), alcohols and acids can be coupled to give esters, even macrocyclic lactones as shown below. In contrast to the Mitsunobu reaction, the reaction leads to retention of stereochemistry at the alcohol. Propose a mechanism that explains the stereochemistry. Why is sulfur necessary here ... 

Macrolactonization can also be achieved by the Mitsunobu reaction [44] with inversion of the configuration of the alcohol. The reaction principle and mechanism are demonstrated in Scheme 24. Addition of triphenylphosphine to diethyl azodicarboxylate (DEAD, 73) forms a quaternary phosphonium salt 74, which is protonated by hydroxy acid 11, followed by phosphorus transfer from nitrogen to oxygen yielding the alkoxyphosphonium salt 76 and diethyl hydrazinedicarboxy-late 75. Then, an intramolecular Sn2 displacement of the important intermediate 76 results in the formation of the lactone 15 and triphenylphosphine oxide. 

A further reaction mechanistically similar to the Mitsunobu reaction as shown in Scheme 26, with the use of AT,iV-dimethylformamide dineopentylacetal (80), can also be employed for macrolactonization [47]. Takei and coworkers [48] applied it to the synthesis of the macrocyclic antibiotic A26771B (55). As shown in Scheme 27, treatment of the linear precursor 82 with 80 in refluxing dichloromethane for 7 h afforded the lactone 83 (39% yield). 

Mitsunobu reaction as well as by mesylation and subsequent base treatment failed, the secondary alcohol was inverted by oxidation with pyridinium dichromate and successive reduction with sodium borohydride. The inverted alcohol 454 was protected as an acetate and the acetonide was removed by acid treatment to enable conformational flexibility. Persilylation of triol 455 was succeeded by acetate cleavage with guanidine. Alcohol 456 was deprotonated to assist lactonization. Mild and short treatment with aqueous hydrogen fluoride allowed selective cleavage of the secondary silyl ether. Dehydration of the alcohol 457 was achieved by Tshugaejf vesLCtion. The final steps toward corianin (21) were deprotection of the tertiary alcohols of 458 and epoxidation with peracid. This alternative corianin synthesis needed 34 steps in 0.13% overall yield. 

Preparative Methods both enantiomers of dihydro-5-(hydroxymethyl)-2(3H) furanone and their trityl derivatives are commercially available but expensive. The simplest and by far most popular method for preparing (5)-dihydro-5-(hydroxymethyl)-2(3H)-furanone (2) consists of enantiospecific deamination of L-glutamic acid and subsequent selective reduction of the resulting carboxylic acid (13) (eq 1). Purification of the intermediate acid (13) by crystallization and not by distillation is recommended in order to secure an excellent optical yield (>98% ee). Likewise, (f )-dihydro-5-(hydroxymethyl)-2(3//)-furanone (1) (>98% ee) can be obtained from o-glutamic acid. As the latter is considerably more expensive than its natural antipode, an appealing option is to convert the (5)-lactone into its enantiomer (eq 2)P Also available and equally useful is an inversion route to (f )-dihydro-5-(trityloxymethyl)-2(3H)-furanone (5) by way of the Mitsunobu reaction (eq 3). ... 

The closure of the lactone must be done with inversion of configuration at the alcohol centre. We should normally use a Mitsunobu reaction for this but mesylation is a good alternative. Mesylatior occurs via the sulfene with retention and then displacement of this excellent leaving group require, inversion and the cis lactone is formed. 

The synthesis of lipstatin 122 is too complex to discuss here in detail but an early stage in one synthesis uses a clever piece of chemoselectivity.23 Kocienski planned to make the P-lactone by a cycloaddition with the ketene 124 and to add the amino acid side chain 123 by a Mitsunobu reaction involving inversion. They therefore needed Z,Z-125 to join these pieces together. This was to be made in turn by a Wittig reaction from 126. The problem now is that 126 is symmetrical and cannot carry stereochemistry and that aldehydes are needed at both ends. 

Hydroxyl protection. By using the title reagent in the Mitsunobu reaction alcohols are protected. The prenyl group of the derived esters is removable by DDQ and subsequent addition of Yb(OTf)3 promotes lactonization to liberate the alcohols. ... 

In the synthesis of D-ristosamine (388), all that is required is inversion of the 5-methyl group of lactone 393. This is readily accomplished by opening the lactone ring with potassium superoxide, acidification to pH 4, and a Mitsunobu reaction. Once again, reduction of the lactone to lactol (71% yield) followed by Wittig reaction and acid hydrolysis (HCl, methanol) affords the desired sugar 388, isolated as the diacetate in 23% yield [124]. 

Protection of the 3-OH with a benzyl group, then removal of the THP group followed by a Mitsunobu reaction affords 976, in which the hydroxyl stereocenter at C-2 is inverted. Conversion of the olefin to an aldehyde results in lactol formation, and subsequent oxidation furnishes lactone 977. Removal of the benzyl protecting group by hydrogenolysis gives diastereomer 978. 

N 0 Me 0 From hydroxymethyl polystyrene by treatment with COClj, HjNNHCOjMe and NBS or Cl,.2i Mitsunobu reactions esters from carboxylic acids and alcohols lactones from hydroxy acids A/-aUcylation of phthalimides, a-alkylation of cyanoacetate carbodiimides from thioureas. ... 

The Miller group [71] continued investigation on the cychzation of /3-hydroxy-O-benzyl hydroxamates in the presence of the Mitsimobu reagent leading to N-benzyloxy- -lactams. The Perrier rearrangement of o-glucal 91 followed by formation of hydroxamate and deacetylation provided a substrate 92 suitable for cychzation. hi the Mitsunobu reaction conditions 92 was converted into the -lactam 93, which was oxidized to the lactone 94 (Scheme 24). 

Lactone substrate 77 was obtained from 57 in one step in 90% yield and its C-4 epimeric analog was prepared by standard inversion procedure. Epoxidation was achieved by action of sodium hypochlorite in pyridine, while conversion to 3-azide required reduction of the epoxide with phenylse-leno(triisopropyloxy)borate, followed by treatment with diphenylphosphory-lazide under Mitsunobu reaction conditions [69]. The acetylated mixture of thioglycosides, obtained from 80, afforded good yield of the desired a-linked antibiotic upon reaction with daimomycinone. All four 2,6-dideoxy-3-azido-L-hexopyranoses were obtained from rhamnal via 4-epimeric lactones. 

Fig. 7 Macrolactonizations mediated by (a) the Mitsunobu reaction (b) the Steglich esterification run in the presence of DMPA, which gives only an urea derivative and (c) high yields of lactones, which are obtained in the presence of a proton source (DMPA, HCl).

The silyl-protected hydroxy-group provides in the diastereoselective [2 + 2]-cydoaddition the asymmetric induction of the ]S-lactone, and is in the Mitsunobu reaction by inversion ofthe stereogenic centre converted into the desired absolute configuration. The end-product, a slightly yellowish oil, stiU contains around 10% of unwanted diastereomers, which cannot be separated off. However, enantiomericaUy pure tetrahydrolipstatin can be obtained by hydrogenation and crystallisation. 

A palladium-catalyzed intramolecular lactonization was used as a key step in the enantioselective synthesis of paeonilactones A and B (Scheme 11.38) [127]. Intramolecular 1,4-diacyloxylation of the cyclohexadienylacetic add 101 afforded 102, which was hydrolyzed to 103 this in turn was transformed to 104 in a Mitsunobu reaction. Hydrolysis of 104 to 105 and stereoseledive alkylation afforded 106, which was converted to paeonilactone A. 

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