Polyoxamic acids synthesis

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... 

Scheme 13. Synthesis of (+)-polyoxamic acid (49) starting from Mannich base 51... 

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. 

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). 

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. 

When only the vic-diol unit of polyoxamic acid (Scheme 4.9) is considered, L-tartaric acid appears as a straightforward precursor for a building block oriented synthesis [11,12] (Scheme 13.18). This leaves the task of addressing a stereoselective generation of the amine-bearing stereogenic center, preferably by substrate-based asymmetric induction (cf. Chap. 10). 

In 2006, Enders and Vrettou [32] reported a concise total synthesis of (-l-)-poly-oxamic acid (82) through an organocatalytic Mannich reaction (Scheme 17.12). Asymmetric Mannich reaction of ketone 79 and Boc-protected imine 80 using L-proline 24 afforded the adduct 81 in 85% yield as a mixture of diastereomers with 92% ee (>98 2 dr). A stereoselective reduction of 81 using L-selectride, followed by ozonolysis and subsequent acid deprotection completed the total synthesis of (-l-)-polyoxamic acid (82). 

Enders D, Vrettou M (2006) Asymmetric Synthesis of (-t)-Polyoxamic Acid via an Efficient Organocatalytic Mannich Reaction as the Key Step. Synthesis 2155... 

Syntheses of polyoxamic acid from pyroglutamic acid and L-tartaric acid and of a 4-amino-2,3-dihydroxyhexanedioic acid from pyroglutamic acid are covered in Chapter 16. Synthesis of imino-alditols are covered in Chapter 18. 

Lee Y, Park Y, Kim M, Jew S, Park H. An enantioselective synthesis of (- -)-polyoxamic acid via phase-transfer catalytic conjugate addition and asymmetric dihydroxylation. J. Org. Chem. 2011 76(2) 740-743. 

Park and coworkers [35] reported the efficient synthesis of (+)-polyoxamic acid (23), a key amino acid moiety of a family of peptidyl nucleoside antibiotics (polyoxins). The key step in this procedure was a stereoselective conjugate addition of glycine Schiff base 14 to acceptor 24 catalyzed by the chiral PTC 25. This gave the key intermediate 26 in quantitative yield and with very high enantioselectivity. The intermediate 26 was then successfully transferred further to yield (+)-polyoxamic acid (23) in seven steps with a high overall yield of 46% (Scheme 3). 

Recently, Park and coworkers [112] described an efficient phase-transfer-catalyzed conjugate addition of the glycine imine ester 65a to ethyl 2-(phenylselanyl)acrylate 83. In the presence of catalyst 13b, the adduct 84 was obtained in almost qtxan-titative yield with 96% ee (Scheme 12.10). The potential application of this addition reaction was demonstrated as an important step in the synthesis of (-l-)-polyoxamic acid. 

Scheme 12.10 Asymmetric total synthesis of (-H)-polyoxamic acid by a phase-transfer catalytic conjugate addition.

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