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Synthesis of (2S,3R)-3-amino-2-hydroxydecanoic acid and its enantiomer: a non-proteinogenic amino acid segment of the linear pentapeptide microginin

Summary A directed manipulation of the functional groups at C3 and C4 of D-glucose was demonstrated to synthesize naturally occurring (2S,3R)-α-hydroxy-β-aminodecanoic acid (AHDA, 2a) and its enantiomer 2b. The enantiomer of 2a is the N-terminal part of the natural linear pentapeptide microginin, which is used as an antihypertensive agent.

We visualized that the structural and the stereochemical symmetry of both enantiomers (2a/2b) is present in D-glucose. The C1-carboxyl carbon atom of 2a is present at the C2 of the D-glucose, and the C4 carbon atom with an alkyl chain in 2a could be built on C5 of the D-glucose (Scheme 1). The required relative stereochemistry of the vicinal hydroxyamino function-ality in 2a at C2 and C3 is embedded at the C3 and C4 of D-glucose, respectively, and needs to be manipulated by usual functional group transformations. Thus, for the synthesis of enantiomers 2a and 2b the corresponding sugar precursors were found to be suitably protected β-L-arabino-pentodialdo-1,4furanose 3a [30,31] and α-D-ribo-pentodialdo-1,4-furanose 3b [32]. There exists a distinct possibility to synthesize these chiron synthons 3a and 3b from the easily available and cheap starting material D-glucose. Our results of the synthesis of both enantiomers 2a and 2b are described herein.

Results and Discussion
As reported earlier, D-glucose was converted to the 3-O-benzyl-1,2-O-isopropylidene-β-L-arabino-pentodialdo-1,4-furanose (3a) in 72% yield (Scheme 2) [30]. While targeting the synthesis of 2a, the Wittig olefination of 3a with n-hexyltriphenylphosphonium bromide and t-BuOK gave olefin 4a as a diasteromeric mixture of Z and E-isomers in the ratio 9.5:0.5 as shown by 1 H NMR of the crude product. The catalytic hydrogenation of alkene 4a with 10% Pd/C in methanol:ethyl acetate (3:2) at balloon pressure gave 4-heptyl-L-threose derivative 5a as a viscous oil in 99% yield [33]. Removal of the 1,2-acetonide group with TFA-water in 5a provided an anomeric mixture of the hemiacetal, which was directly subjected to oxidative cleavage by using sodium metaperiodate in acetone-water (to cleave the anomeric carbon) followed by a treatment with sodium borohydride to give triol 6a as a viscous oil in 78% overall yield in three steps [34]. The primary hydroxy group of triol 6a was selectively monosilylated with t-butyldiphenylsilyl chloride to give 7a. Subsequently, the secondary hydroxy group in 7a was converted to azido derivative 8a with an inversion of the configuration by using diphenylphosphoryl azide in the presence of DBU in 88% yield [35]. Cleavage of the silyl functionality in 8a with n-tetrabutylammonium fluoride offered azido alcohol 9a as a viscous oil. The azido alcohol 9a was oxidized to the corresponding acid by using RuCl 3 ·3H 2 O/NaIO 4 to give 10a [36].

Conclusion
In conclusion, we demonstrated a practical approach for the synthesis of both enantiomers of AHDA (2a and 2b) to obtain the stereochemistry required for the α-hydroxy-β-amino acid. Our method starts from D-glucose by an easy manipulation of its functional groups at C3 and C4. In addition, the chiral core (α-hydroxy-β-amino acid) in 2a is present in several biologically active compounds such as taxol, balanol and bestatin. Therefore, this methodology could be potentially exploited for the synthesis of the chiral segment of these compounds.

Supporting Information
Supporting Information File 1 Experimental procedures.

Supporting Information File 2
Copies of NMR spectra.