PMC

Iwakura et al. reported that the bis-hydrazonoyl chloride IV reacted with various olefinic dipolarophiles such as allyl alcohol, methyl 1-methylacrylate and N-phenyl maleimide in benzene in the presence of triethylamine yielded the corresponding bis-cycloadduct 53-55 ().

Reagents and conditions: (a) benzenesulfonyl chloride, DIPEA, CH₂Cl₂, 97%; (b) SeO₂, dioxane, 80 °C, 91%; (c) In powder, allyl bromide, NH₄Cl(aq), THF, 96%; (d) K₂OsO₄·2H₂O, lutidine, dioxane, H₂O, then NaIO₄, 75%; (e) methylamine(aq), NaBH(OAc)₃, MeOH, H₂O, 81%; (f) methyl adipoyl chloride, DIPEA, CH₂Cl₂, 59%; (g) carbonyldiimidazole, DMF then 6-amino-N-(prop-2-ynyl)hexanamide, DIPEA, DMF, 81%; (h) 0.2 M NaOH(aq), THF, MeOH, 82%; (i) N-hydroxysuccinimide, EDCI, DMF, 48%.

Application of a B/C/P approach starting from proline 3/3^′ to give compounds 8–14. From 3^′, (i) (S)-allylglycine methyl ester, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI), Oxyma, Et₃N, CH₂Cl₂, 89%; NaH, MeI, DMF, 89%; (ii) Grubbs II, CH₂Cl₂, reflux, 34%; TFA; (iii) allylamine, EDCI, Oxyma, Et₃N, CH₂Cl₂, 91%; NaH, MeI, dimethylformamide (DMF), 72%; (iv) Grubbs II, toluene, 60%; TFA. From 3, (v) allyl isocyanate, Et₃N, CH₂Cl₂, 70%; (vi) NaH, DMF, 93%; (vii) 2-chlorosulfonyl chloride, Et₃N, CH₂Cl₂, 62%; (viii) Grubbs II, CH₂Cl₂, reflux, 92%; LiOH, THF, 53%; (ix) prop-2-ene-1-sulfonyl chloride, Et₃N, CH₂Cl₂, 44%; (x) Grubbs II, CH₂Cl₂, reflux, 96%; LiOH, THF, 71%; (xi) LiAlH₄, THF; tert-butyldimethylsilylchloride, Et₃N, CH₂Cl₂ (24% over two steps); 2-chlorosulfonyl chloride, Et₃N, CH₂Cl₂, 33%; (xii) tetrabutylammonium fluoride, THF, 45%; (xiii) (S)-N-Boc-allylglycine, EDCI, Oxyma, Et₃N, CH₂Cl₂, 48%; (xiv) Grubbs II, CH₂Cl₂, reflux, 41%; TFA.

Cyclic ntla cMO synthesis. a) allyl TMS, TiCl₄, CH₂Cl₂, 98%; b) O₃, MeOH; c) NaBH₄, MeOH, 74% over 2 steps; d) TsCl, pyridine, 63%; e) methylamine, THF, 87%; f) methyl adipoyl chloride, DIPEA, CH₂Cl₂, 57%; g) 1,1′-carbonyl diimidazole, CH₂Cl₂; h) ethylenediamine, CH₂Cl₂; i) 2-chloroacetyl chloride, Et₃N, CH₂Cl₂, 54% over 3 steps; j) LiOH, THF, H₂O; k) N,N′-disuccinimidyl carbonate, pyridine, CH₃CN, 68% over 2 steps; l) 5′-amine, 3′-alkyl disulfide ntla MO (21-, 23-, or 25-base), 0.1 M Na₂B₄O₇ pH 8.5, DMSO, 69–95%; m) TCEP resin, 0.1 M Tris-HCl buffer, pH 8.4, 84–92%.