Diastereoselective Allylstannane Additions to (S)-5,6-Dihydro-2H-5-phenyloxazin-2-one. A Concise Synthesis of (S)-β-Methylisoleucine

Abstract

The addition of allyl stannanes to (S)-4,5-dihydro-5-phenyl-2 H-oxazinone (3) was achieved under Brønsted acid catalysistogive 2-allylmorpholinones with high diastereoselectivity (up to dr14.2:1).The product of dimethylallyltributylstannane addition to 3 was converted to L-β-methylisoleucine, an α-amino acid residue found in the complex, biologically-active marine-derived peptides polytheonamides A and B and polydiscamides A-C.Marine peptides often contain highly modified amino acids, including chlorinated amino acids, 1 β-amino acids 2 and highly-substituted β,β-dimethyl-α-amino acids. 3 L-tert-Leucine (1a) and L-tert-amylglycine (β-methylisoleucine, 1b) occur in the 48-mers polytheonamides A and B; two highly cytotoxic β-helix, membrane-pore forming peptides from the marine sponge, Theonella swinhoei. 4 The peptides polydiscamide A from Discodermia 5a (2 , Figure 1), and the polydiscamides B-C from the sponge Ircinia ,5b which are the first non-endogenous inhibitors of sensory neuron-specific G-protein coupled receptors (SNSRs), also contain 1a and 1b. 6 The amino acid γ-hydroxy-tert-leucine (L-pantonine, 1c) was proposed as an intermediate in the biosynthesis of pantoic acid. 7 With an eye to the synthesis of highly biologically active, cyclic peptides, we sought to fulfill a need for a general synthesis of highly-β-branched α-amino acids.Racemic syntheses of tert-alkyl-α-amino acids have been reported. 8 Asymmetric preparation of L-1a and L-1b was achieved by tandem-enzyme coupled reductive amination of the tmolinski@ucsd.edu.

Preparation of α‐Amino Acids by Oxidative Oxazoline–Oxazinone Rearrangement–Hydrogenation (OOOH). Scope and Limitations

“…The poor yield observed for hydrogenation of the glutaric‐acid‐derived morpholinone 12e (20 %; Table 2, entry 6) possibly arises from side‐reactions involving cyclization of the terminal carboxymethoxy group to the γ‐lactam. ( S )‐ tert ‐Amylglycine ( 13a ; Table 2, entry 1) was obtained in comparable yield (50 %, two steps from 5( R )‐oxazinone 11a ) to that previously reported (56 %)1d for the diastereoselective nucleophilic addition of tributyl(dimethylallyl)stannane to the corresponding parent 5( S )‐oxazinone ( 11d , R=H) followed by hydrogenolysis. Finally, we noted that OOOH provides the first asymmetric synthesis of 13b ,14 a valuable amino acid for the synthesis of the investigational anticancer drug HTI‐286,10 in good overall yield from 3,3‐dimethyl‐3‐phenylpropanoic acid16 (39 %, five steps; Table 2, entry 2) with essentially complete stereocontrol.…”

“…Similar conformational preferences of CH 2 COOMe and indol‐3‐yl groups—specifically, differential rotameric preferences for gem ‐dimethyl and sp 2 groups—led to comparable d.r. values for the hydrogenation of 11e , 11f , 11g (d.r.>80:1), much higher than those of 11a (d.r.=8.7) and other 2‐ tert ‐alkyloxazinones (d.r.=13:1) 1a,d. The effect was diminished in the hydrogenation of 11c (d.r.=9:1) where the 1‐phenylethyl substituent is secondary, but recovered in 11d (d.r.>80:1) where the all‐sp 2 , conjugated substituent and planarity of the C2C3(N) para ‐hydroxyphenyl array exposes the singular influence of the C‐5 phenyl directing effect 17…”

Studies Toward the Total Synthesis and Stereochemical Assignment of Microspinosamide

“…: -42.5 (c 1.0 CHCl 3 ) 1 H NMR (500 MHz,CDCl 3 ) δ 7.40 -7.28 (m, 5H, Ph), 6.11 (dd, J = 17.5 Hz, J = 10.9 Hz, 1H), 5.15 -5.13 (m, 2H), 4.43 (m, 1H), 4.25 (dd, J = 10.6 Hz, J = 9.0 Hz, 1H), 3.50 (s, 1H), 1.95 (brs, 1H), 1.33 (s, 3H), 1.32 (s, 3H). These data were in agreement with those previously reported Pigza et al2 fluoren-9-yl)methoxy)carbonyl)amino)-3,3-dimethylpentanoic acid 10Morpholinone S4 (85 mg, 0.35 mmol), Pd(OH) 2 (56 mg, 0.09 mmol, 20% Pd content), 1 M HCl (1.6 mL), and MeOH (9.5 mL) were added to a thick-walled flask and placed in a Parr hydrogenation apparatus, pressurized to 90 psi with H 2 (~6 atm). The reaction was allowed to stir for 3 h, then filtered through celite.…”

Synthesis and photo-physical properties of fluorescent 1,3,5-triazine styryl derivatives

“…Organic fluorescent heterocyclic chromophores have a wide range of applications in molecular probes [ 1 ], fluorescent markers [ 2 ], organic light-emitting diodes (OLED)[ 3 ], photovoltaic cells [ 4 ] and in traditional textile and polymer fields [ 5 ]. Electron donors like triphenylamine [ 6 ], diphenylamine [ 7 ] 1,3,5-triazines [ 8 ] and carbazoles [ 9 ] with high electron mobility, thermal and photochemical stability are commonly used as hole-transporting materials or light-emitting materials for balanced charge injection for above mentioned application.…”