Hydroxylated pipecolic acids

The five-membered ring can also be formed by intramolecular nucleophilic attack of an alkoxide on a carbamate such as for the formation of 196 from 195 <1997T9553>, by dehydration of fV-carbamate-pipecolic acid derivatives <2002EJO3936>, by treatment of amino-amides under Eschweiler-Clarke conditions <1999TA3371>, or by treatment of hydroxyl aminonitriles with silver trifluoroacetate <2002JA2951> (Scheme 57). 

Synthesis from i-threose 4-C -(fm-Butyldiphenylsilyl)-2,3-(9-isopropylidene-L-threose (49) has been used for the synthesis of 1-deoxygalactostatin (4) and the nnnatural pipecolic acid derivative 56 (Scheme 11). Compound 49, obtained from L-tartaric acid, was treated with tin(ll) azaenolate 51, obtained from 50 by treatment with stannous chloride, to afford compound 52 in 79% yield with a diastereomeric excess of 90%. Benzylation of adduct 52 led to 53. After removal of the silyl group, the hydroxyl group... 

Synthesis from o-mannose Syntheses of a-homonojirimycin (1), 6-cp/-a-homo-mannojirimycin (39) and the pipecolic acid derivative 36 from D-mannose have been reported (Scheme 5). The azidolactone 31, ° prepared from diacetone mannose (30), nnderwent selective removal of the terminal isopropylidene gronp, followed by selective protection of the resnlting primary hydroxyl gronp with fcrt-butyldimethylsilyl chloride to... 

The first total synthesis by the Merck group was accomplished via coupling of the C10-C19 and C20-C34 segments, attachment of (5 )-pipecolic acid to the C26 hydroxyl group, aldol addition of glycolate derivatives to the CIO aldehyde, and final macrolactamization (Fig. 5). 

The first total synthesis of rapamycin (2) was accomplished by Nicolaou et al. in 1993. The synthetic feature includes esterification of the C34 hydroxyl group of the C21-C42 segment with pipecolic acid, amide formation with the C8-C18 segment, and extremely novel macrocyclization by double Stille coupling using vinyl stannane at the Cl8 and C21 positions (Fig. 6). 

Chemical conversions of marcfortine to paraherquamides have been achieved [415]. Utilising various soil-derived microorganisms, individual hydroxylation at carbon atoms 5, 10, 12, 14, 15, 16 and 27 has been realized [416] but no improvement on the activity of (244) was observed. A study of the biosynthesis of (244) has shown that it is derived from methionine, tryptophan, lysine and two isoprene units, the latter two being derived from acetic acid. The pipecolic acid moiety arises from lysine via a-ketoglutarate [417]. 

The elimination of the 6-amino group could occur via the action of an amine oxidase as has been suggested orPisum sativum (Mann and Smithies, 1955) or via the formation of saccharopine (Nabeta et al., 1973). Labeled pipecolic acid was found to serve as a precursor for the hydroxypipecolic acids of Umonium (Larher, 1976) and this conversion could proceed via the hydroxylation of 4,5-dehydropipecolic acid (baikiain). 

The reactivity of the compounds to be derivatized clearly plays an equally important part. Thus, for example, ephedrine, pseudoephedrine and analogues were acylated with TFAA for 5 minutes at 60 "C [57], tricyclic antidepressants with HFBA for 10 minutes at 60 °C [58], the methyl esters of pipecolic acid, proline, glutamic acid and y-aminobutyric acid with HFBA for 20 minutes at 150 °C [59], and catecholamines (after methylation of the j8-hydroxyl) with PFPA for 15 minutes at 80 °C [60]. 

Hydroxylation of Pipecolic Acid Using Recombinant Cells of E. coli Expressing Proline-trans-4-hydroxylase from Dactylsporangium sp. 

Hydroxylation of L-pipecolic acid 41 by recombinant ceiis of co/i expressing proiine frans-4-hydroxyiase [55]. 

C. Klein, W. Hiittel, A simple procedure for selective hydroxylation of L-proline and L-pipecolic acid with recombinantly expressed proline hydroxylases, Adv. Synth. Catal. 353 (8) (2011) 1375-1383. 

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