Polyoxamic acids

Aziridine lactone 235 (Scheme 3.87) underwent ring-opening with allyl alcohol to give a 53% yield of a-amino lactone 236, which was successfully transformed to the unnatural enantiomer of polyoxamic acid (—)-237 [32],... 

The reaction protocol was further extended to the concise synthesis of poly-oxamic acid, the unique polyhydroxyamino acid side-chain moiety of the antifungal polyoxin antibiotics (63). Treatment of the template 205 under standard thermal cycloaddition conditions with (5)-glyceraldehyde acetonide led to the formation of a single diastereoisomer 208 in 53% yield. Subsequent template removal released polyoxamic acid 209 in essentially quantitative yield. This represents a matched system, with the mismatched system leading to more complex reaction mixtures (Scheme 3.70). 

An application of the deracemization strategy has provided efficient entry to a novel amino acid substituent of the antifungal agents, polyoxins and nikkomycins, as shown in Scheme 8E.20. The versatile five-carbon building block was obtained from phthalimidation of the hydroxymethyl-substituted epoxide in 87% yield and 82% ee. Straightforward synthesis of polyoxamic acid was then accomplished by subsequent dihydroxylation and selective oxidation of the alkylation product. 

The stereoselective synthesis of (+)-polyoxin J is accomplished by Gosh in 24 steps and 3 % overall yield. The key intermediates are protected thymine polyoxin C 8 and the 5-Ocarbamoyl polyoxamic acid 2, which were synthesized from D-ribose and dimethyl L-tartrate. Key steps are two different epoxidation reactions, one carried out with MCPBA and the other under Sharpless conditions with the D-(-)-tartrate. Both epoxides are opened with diisopropoxytitanium diazide. The coupling of the two fragments was realized with the BOP reagent 37. This synthesis provides an easy access to the synthesis of various (+)-polyoxin J analogs for biological evaluation. 

Enders D, Seki A (2002) Proline-catalyzed enantioselective Michael additions of ketones to nitrostyrene. Synlett 2002 26-28 Enders D, Vrettou M (2006) Asymmetric synthesis of (+)-polyoxamic acid via an efficient organocatalytic Mannich reaction as the key step. Synthesis 13 2155-2158... 

Based on our previously developed organocatalytic Mannich methodology (Enders et al. 2005b) we planned a synthetic strategy towards (+)-polyoxamic acid (49) starting from a suitable Mannich base, which would utilize a diastereoselective reduction of the ketone functionality to the corresponding secondary alcohol and an oxidation step to con-... 

Fig. 5. Several members of the polyoxin family and of (+)-polyoxamic acid (49)...

Ethyl lactate has also been used as a chiral fragment for numerous other studies. Included are synthetic efforts relating to salenomycin, (-)-biopterin, (+)-polyoxamic acid, jaspamide, the enantiomeric 2-pentanols, pumilitoxin B, D-ristosamine, protomycinolide IV, and tirandamycin. ... 

EtsN in CH2CI2 in the presence of 4-dimethylaminopyridine (Scheme 13.68). Dihydroxylations of the trimethylsilyl ethers of 217 and 218 generate the 4-amino-4-deoxy-heptono-1,4-lactam derivatives 219 and 220, respectively [121]. Lactam hydrolysis of 219 with LiOH, followed by the Malaprade diol cleavage with NaI04 and further oxidation and deprotection, allows the preparation of 4- p/-polyoxamic acid [122]. Lactam 217 and its enantiomer derived from (5 )-24 have been converted into all four stereomers of cw-l,2-dihydroxypyrrolizidine [123]. Compounds 217 and 218 have been used also to prepare the rm/i5 -2,3-c/5 -3,4-dihydroxyprolines [124,125]. 

The sulfinimine-mediated asymmetric Strecker reaction was developed by F.A. Davis et al. This method involves the addition of ethylaluminumcyanoisopropoxide to functionalized sulfinimines and the resulting diastereomeric a-amino nitriles are easily separated. Subsequent hydrolysis directly affords the enantiopure a-amino acids. This protocol was applied for the synthesis of polyoxamic acid lactone. ... 

Savage, I., Thomas, E. J. Asymmetric a-amino acid synthesis synthesis of (+)-polyoxamic acid using a [3,3]allylic trifluoroacetimidate rearrangement. J. Chem. Soc., Chem. Common. 1989, 717-719. 

Davis, F. A., Prasad, K. R., Carroll, P. J. Asymmetric Synthesis of Polyhydroxy a-Amino Acids with the Sulfinimine-Mediated Asymmetric Strecker Reaction 2-Amino 2-Deoxy L-Xylono-1,5-lactone (Polyoxamic Acid Lactone). J. Org. Chem. 2002, 67, 7802-7806. 

Hydrogenolysis. A neat approach to syn-3-hydroxy a-amino acids involves condensation of (5)-5-phenylmorpholin-2-one with excess aldehyde, methanolysis, removal of the A-(hydroxymethyl)benzyl unit by hydrogenation with Pd(OH)/C and 1 equiv of CF3COOH, and saponification. The method can be used for access to polyoxamic acid. 

The combination of lactic acid and tartaric acid has been used in the synthesis of (+ )-polyoxamic acid (435), the unusual amino acid component of polyoxin B (Scheme 60). The lactic acid component, ylide 429, is available from 427 by hydrolysis, conversion to thioester 428, and reaction with excess methylenetriphenylphosphorane. Wittig olefination with L-tartrate-derived aldehyde 430 gives the (E)-enone 431. Reduction to syn-alcohol followed by treatment with trifluoroacetonitrile affords 432. 

The synthesis of (-h )-polyoxamic acid (435), the unusual amino acid component of polyoxin B, incorporates backbone assembly via a Homer- Emmons olefination of L-tartrate-derived aldehyde 430 with (i )-lactate-derived jS-ketophosphonate 914 [101] (Scheme 122). The key introduction of the chiral amine stereocenter is accomplished by a trifluoroacetimidate rearrangement, outlined in Scheme 60 (Section 1.4.7.2). 

The epoxide 100 generated a symmetrical r-allylpalladium intermediate and reacted with phthalimide (99) using Trost L-1 to provide 101 in 87 % yield with 82% ee, and polyoxamic acid was synthesized from 101 [39]. 

Tunicamycin V (formerly "A") (26) has been prepared, together with 3 minor components of the complex and other analogues in the key step, the glycosyl chloride (27) was condensed with the reducing amino-sugar derivative (28), which was then conventionally converted to (26). Another communication reports a total synthesis of polyoxin J (29), converting 4-0-benzyl-2,3-0-isopropy-lidene-L-threose to deoxypolyoxin C (30) on the one hand and to the 5-0-carbamoyl-polyoxamic acid derivative (31) on the other, these... 

In Scheme 4.9 the core structure of polyoxamic acid is shown. Suggest suitable chiral building blocks for its synthesis. 

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