Pyroglutamic acid derivatives

Nva) nucleoamino adds Fmoc-Nva -OH (15) and Fmoc-Nva -OH (18). Both of these nucleoamino acids have now been synthesized regioselectively in good overall yields starting from the known pyroglutamic acid derivative 10 via the sequences shown in Scheme 5.2 [44]. Preliminary experiments have shown that these two nudeoamino acid derivatives can be incorporated into our SPPS without the need for protection of the exocyclic NH2 groups [45]. 

Derivatives of the pyrrolooxazole were obtained either from Pro after reaction with phenylglyoxal to give a mixture of isomers 80 (87TL6077) or from a pyroglutamic acid derivative [89H(29)2089],... 

Due to the low reactivity of the nitrogen, incorporation of the pyroglutamic acid into endo-positions by stepwise chain elongation is difficult (see reft49 and refs cited therein). It may be achieved using suitably protected aminoacyl-pyroglutamic acid derivatives as dipeptide synthons. These are accessible in satisfactory yields, e.g. by acylation of pGlu-OBzl with N-protected amino acid pentafluorophenyl esters in the presence of NaH or LiHMDS. 49 ... 

The double diastereoselection of cycloaddition of chiral nitrones with Oppolzer s sultam acrylamide was studied and the adducts were converted into 4-hydroxy-pyroglutamic acid derivatives <02TA167,02TA173>. 

Somfai and Ahman have applied an intramolecular allyl silane addition to an AT-sulfonyl iminium ion as a key step in an alternative synthesis of (+)-anatoxin A [43]. Thus, L-pyroglutamic acid-derived compound 55 was homologated to aldehyde 126 and then to allyl silane 127 (Scheme 24). Using titanium tetrachloride, 127 could be cyclized in good yield to bicyclic olefin 128, which was converted to the alkaloid. 

Aberhart and Weiller (183) used (2/ S,3S)-[4- Ci]valine 179 prepared as described in the previous section to synthesize samples of (2S, 4S)- and (2R, 4S)-[5- Ci]leucine 205. More recently, in need of a synthesis of large quantities of labeled leucine, we have devised a synthesis of (2S,4/ )-[5,5,5- H3]leucine 205b, starting from the pyroglutamic acid derivative 206 (184). This is shown in Scheme 59, chirality being achieved by diastereoselective catalytic reduction 207 208. 

In the later work, Coward and coworkers carried out a study of electrophilic fluorination of pyroglutamic acid derivatives. The results provided an alternative route to fluorinated pyroglutamic acids and derived fluoroglutamic acids." " Conditions were found that led to diastereoselective monofluorination to produce 40, but attempts to carry out difluorination of the substrate were unsuccessful. The bicyclic... 

Konas, D.W. Coward, J.K. Electrophilic fluorination of pyroglutamic acid derivatives application of substrate-dependent reactivity and diastereoselectivity to the synthesis of optically active 4-fluoroglutamic acids. J. Org. Chem. 2001, 66, 8831-8842. 

SCHEME 7.37 Synthesis of pyroglutamic acid derivatives by convertible indole-isonitrile methodology. 

A double-Michael addition of amide-tethered dicarboxylic acids 60 with aromatic alkynones 61 could lead to highly functionalized pyroglutamic acid derivatives 62 (Scheme 2.17). With substoichiometric quantities of Mg(OTf)2 or Ni(acac)2 as additives, Lam and coworkers developed a novel reaction that provided the corresponding products with good levels of trans diastereoselectivity [30]. 

Scheme 2.17 Synthesis of pyroglutamic acid derivatives via double-Michael reactions.

Several imino-alditols have been prepared from non-carbohydrate sources. 2,S-Dideoxy-2,S-imino-D-mannitol has been synthesized from a pyroglutamic acid derivative (see Vol. 27, p. 209, ref. 59 for the use of pyroglutamic acid in the synthesis of other imino-alditols), and 1-deoxy-L-allonojirimycin has been made from a protected L-serine derivative. A protected D-serine aldehyde provided access to a l,2,4-trideoxy-l,4-imino-D-eryrAro-pentitol derivative for incorporation into DNA, and reduction of the minor natural amino acid, 4-L-hydroxyproline, gave l,3,4-trideoxy-l,4-imino-D-eryrAro-pentitol which, after Af-acylation with a fluorescent probe, was incorporated into oligonucleotides. ... 

The synthesis of piclavines A1 (2499) and A2 (2500) by Stevenson and coworkers capitalized on their prior investigations into the synthesis of 5-substituted indolizidinones, " which had made use of the conversion of the (S)-pyroglutamic acid derivative 2509 into the unsaturated... 

Ye and coworkers have since reported a wide range of cycloadditions using different electrophilic partners, all in the presence of pyroglutamic acid-derived triazolium catalysts [120]. A noteworthy example is represented by the enantioselective formal [4-1-2] cycloaddition of ketenes with enones 151 to obtain dihydropyranones... 

In 2005, Honda et al. pubhshed a first total synthesis of a quinohzidine alkaloid using RCM as one of the key steps, namely, (—)-deoxynupharidine (246) [80]. The alkaloid was isolated from plants of the genus Nuphar and exhibited amongst others immunosuppressive activity. Its synthesis commenced with a stereoselective construction of the enantiopure 5,6-disubstituted piperidinone building block 244 by modification and ring expansion of the protected D-pyroglutamic acid derivative 243 (Scheme 2.53). Subsequent RCM of 244 (catalyst [Ru]-II, benzene, 60°C) afforded quinolizidinone 245 in 96% yield, whereafter three consecutive steps led to the natural product itself... 

---