Synthesis and application of L-N-Boc-N-methyl-β-hydroxyvaline in the preparation of a depsipeptide

Abstract

Enantiopure (>99% ee) L-N-tert-butyloxycarbonyl-N-methyl-β-hydroxyvaline (2) was synthesized in six steps and 43% overall yield from D-serine methyl ester (5). Methyl (4S)-N-(9-phenylfluoren-9-yl)-oxazolidine-4-carboxylate (7) was prepared in two steps and 73% yield by N-phenylfluorenation of 5 followed by cyclization of N-(PhF)amino alcohol 6 with formaldehyde and catalytic p-toluenesulfonic acid (PhF = 9-phenylfluoren-9-yl). The addition of MeLi to oxazolidine carboxylate 7 produced the tertiary alcohol 8 in 91% yield. Oxazolidines 8 equilibrated with oxazolidine 9 under acidic conditions. Reduction of pure 8 or the mixture of oxazolidines 8 and 9 with NaCNBH3 and hydrochloric acid in anhydrous dioxane afforded N-methyl amino diol 11 in 86%–92% yields. Attempts to selectively oxidize N-(PhF)amino diol 11 were unsuccessful; however, hydrogenation of 11 in the presence of di-tert-butyl dicarbonate gave the corresponding N-(Boc)amino diol 12 in 82% yield. Selective oxidation of diol 12 was performed using a cocktail containing TEMPO free radical, NaClO2, and NaOCl to give L-N-Boc-N-methyl-β-hydroxyvaline (2) in 87% yield. Coupling of β-hydroxyvaline 2 and (S)-2-hydroxy-3-methylbutanoate (15) was accomplished by using the methodology of Mitsunobu to provide depsipeptide Boc-(S)-HOMeVal-(R)-Hmb (4) for use as a building block in the synthesis of the cyclic antifungal depsipeptide aureobasidin B.Key words: N-methylated amino acid, serine, depsipeptide, aureobasidin.

Mitsunobu and Related Reactions: Advances and Applications

“…Due to the large number of other applications involving similar inversion/epimerization, we only list them here; the structural drawings pertaining to these references are given in the Supporting Information (Table S1). These pertain to the synthesis of (i) pregnanone derivatives, (ii) glucosphingolipids, (iii) pyrrolidine-amide oligonucleotide mimics, (iv) tubronic acid, (v) enantiopure butanoates, (vi) macroviracins, (vii) reduced products of cis - and trans -hexahydronaphthalenones, (viii) stereoinversion of myo -inositol into scyllo -inositol, (ix) orthogonally-protected and unprotected depsipeptides such as l -Lys- d -Ala- d -Lac and Boc-( S )-HOMeVal-( R )-Hmb, (x) (2 S ,3 S ,4 R )-4-( tert -butyldimethylsilyloxy)-2,3-isopropylidenedioxy-4-phenylbutanoate, (xi) dihydroxycholesterol, (xii) the acetate of the triol derived from jasminine, (xiii) stereochemically inverted products of xylofuranosyl derivatives, (xiv) 6- epi- aucubin, (xv) hydroxyethylene dipeptide isosteres (e.g. L-682,679), (xvi) orobanchol (a germination stimulant), (xvii) long chain pentadeca-1,3,5,7,9,11,13,15-octols (16 diastereomers), (xviii) mycalamide A (natural product), (xix) murisolin (natural product), (xx) leucascandrolide A (natural product with a sterically congested carbon), , (xxi) l -lyxose esters, (xxii) cryptophycin (5-hydroxy acid subunit), (xxiii) polycyclic carbohydrates, (xxiv) protected aminooxyprolines, (xxv) carbahexopyranose stereoisomers, (xxvi) deoxynucleic guanidine (DNG) oligonucleotide, (xxvii) D-hica, a component of kulokekahilide-2, (xxviii) methylsulfonate esters, (xxix) (4 R ,5 S )- and (4 S ,5 R )-muricatacins, (xxx) trioxilins, (xxxi) functionalized β-C-glycosyl aldehydes (a part of ambruticin), (xxxii) pyrrolidinols, (xxxiii) carbocyclic nucleosides, (xxxiv) Δ 2 -OPC-8:0 (a substituted cyclopentanone derivative), (xxxv) fluorescence-labeled probes based on phyllanthurinolactone [in these cases, 4-dimethylaminophenyldiphenylphosphine ( 2 ) instead of Ph 3 P worked better], (xxxvi) (+)-cardiobutanolide, (xxxvii) 3-amino-2,3,6-trideoxysugars, (xxxviii) sesquiterpene lactones, (xxxix) 3-methylcyclopentadecanol, (xl) optically active β-methyl-γ-alkyl-γ-butyrolactone, (xli) chiral P,N-ligands with a cyclohexane backbone, (xlii) optically active aminobenzindanol, (xliii) cyclopenta[ d ]pyridazinediol, (xliv) 4-hydroxytetrahydropyranone, (xlv) alkynic esters as precurso...…”

Synthesis of Chiral (Indol‐2‐yl)methanamines and Insight into the Stereochemistry Protecting Effects of the 9‐Phenyl‐9‐fluorenyl Protecting Group

“…[23] A compound derived from 10c has previously been described as enantiopure. [27] Therefore we could safely assume that the described synthetic routes to the (indol-2yl)methanamines presented herein yields compounds with an ee of at least 99 %. As a final conclusion, the successful synthesis of enantiopure (indol-2-yl)methanamines using four structurally very different amino acids shows greater generality for this substance class than previously published procedures.…”

“…[24] Methyl esters 9a-b were subjected to 9-phenyl-9-fluorenylation, following a known literature procedure developed for the dimethyl ester of aspartic acid. [25] Methyl ester 10c was synthesized according to a known literature procedure, [26,27] The esters 10a-c where then transformed into the corresponding Weinreb amides 11a-c, using a Grignard base and the HCl salt of N,O-dimethylhydroxylamine.…”

“…General Information: Compounds 12, [48] 13d, [23] 10c (experimental details are presented), [26,27] 10d, [23] 23 [25] as well as 24 [49] were prepared using known literature procedures. All experiment using moisture sensitive chemicals were performed in flame dried glass ware under argon atmosphere.…”

Total Syntheses of Nannocystins A and A0, Two Elongation Factor 1 Inhibitors

“…The assembly of peptide motif 13 started with the synthesis of 15 via Mitsunobu reaction between the known compounds 16 and 24 (Scheme ). , Deprotection of tert -butyl carbamate 15 furnished ammonium salt 25 . N -Fmoc-protected N -methyl- l -isoleucine ( 26 ) was successfully coupled with d -tyrosine benzyl ester, affording dipeptide 27 in 95% yield.…”