A convergent synthesis of [S-(R,S)]-2-[4-[(4-methylpiperazin-1-yl)carbonyl]phenoxy]-3,3-diethyl-N-[1-[3,4-(methylenedioxy)phenyl]butyl]-4-oxo-1-azetidinecarboxamide (L-694,458, 1), a potent human leukocyte elastase inhibitor, was achieved via chiral synthesis of key intermediates: (S)-3,3-diethyl-4-[4'-[(N-methylpiperazin-1-yl)carbonylphenoxy]-2-azetidinone (2) and (R)-alpha-propylpiperonyl isocyanate (3). Synthesis of beta-lactam 2 was achieved by a novel enantioselective lipase hydrolysis of ester 5 to produce (S)-3,3-diethyl-4-(4'-carboxyphenoxy)-2-azetidinone (6) (60% yield, three cycles, 93% ee) with isolation, epimerization, and recycling of the undesired (R)-ester 5. Isocyanate 3 was prepared by chiral addition of Zn(n-Pr)(2) to piperonal (98% yield, 99.2% ee), azide displacement and reduction to (R)-alpha-propylpiperonylamine (11) (58% yield, 85% ee), crystallization as the D-pyroglutamic acid salt (92% yield, 98.2% ee), and isocyanate formation (98% yield) with phosgene.

inosine (Ino) and 5'-GMP complexes such as [(NH3)2Pt(InoH_1)]+ and [(NH3)2Pt(GMPH_i)]"; there were attributed to polynuclear complex formation.12•13 Furthermore, there is clear evidence that none of the species formed during the reaction is a Pt complex with two 5'-GMP molecules bound via N7 of the guanine ring to the Pt atom from both 'H and l95Pt NMR data of the m-[Pt(NH3)2(5'-GMP)2] complex. The latter exhibits a H8 proton resonance at 3.931 ppm and a 195Pt resonance of-2451.3 ppm which is considerably shifted to high field from the 195Pt resonances of species IG/IIG and IIIG (see Table III). Further, the resonances for the HI' protons in the c«-[Pt(NH3)2(5'-GMP)2] complex are at 2.143 ppm, 0.020 ppm to high field of the corresponding resonance in free 5'-GMP (2.163 ppm), while in species IG, IIG, and IIIG the HI' signals are at ca. 2.28 ppm which is to low field of the corresponding free signal.From the structures of species IG/IIG given in Figure 9 in which the Pt atom is bound to N7 of the guanine ring, one would expect the 195Pt chemical shift of species IG/IIG to be given approximately by the mean of the 195Pt chemical shifts of cis-[Pt(NH3)2Cl2] and m-[Pt(NH3)2(5'-GMP)2]; this has a value of-2306.4 ppm which is in excellent agreement with the measured value of -2302.0 ppm.Comparison of the Kinetics of the Reactions of 5'-AMP and 5'-GMP with Excess c/s-[Pt(NH3)2Cl2] in the Presence of KC1. A comparison of the kinetics of the reactions of 5'-AMP and 5'-GMP with excess m-[Pt(NH3)2Cl2] in the presence of KC1 at 80 °C leads to the following observations. Tables I and II show the relationship klG ~klA > k3A = k4A > k2A for the second-order association rate constants, which implies that the dissociation of a Cl atom from ris-[Pt(NH3)2Cl2] is not rate limiting. Considering only the 5'-AMP reaction with m-[Pt(NH3)2Cl2], we observe that the association rate constant for binding to N7 (k]A) is larger than that for binding to N1 (k2A), a finding which correlates inversely with the smaller pA of N7 compared to N1 of the adenine ring.25 However, once a Pt atom is bound to either N1 or N7, the association rate constants (k3A and k4A) for binding to the remaining site are equal. This implies an electronic redistribution upon binding of a Pt atom to either N1 or N7, such that the reactivity toward cri-[Pt(NH3)2Cl2] of the remaining available site is less than that of N7 but greater than that of N1 in free 5'-AMP. Considering the schemes for the reaction of 5'-GMP with excess dr-[Pt(NH3)2Cl2], it is clear that species IG and IIG could either be formed simultaneously (as in the case of species IA and 11A in the 5'-AMP reaction) or in sequence. Given our proposed structures for species IG and IIG (Figure 9), the latter seems unlikely. Moreover, it is likely that the association rate constants for the formation of the two rotamers, IG and IIG, would be equal and given by k]G/2. Assuming this assumption is correct, we note the relationship k1A > klG/2 > k2A for the second-order association rate constants for the binding of ...

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Compound 1 is a p38 MAP kinase inhibitor potentially useful for the treatment of rheumatoid arthritis and psoriasis. A novel six-step synthesis suitable for large-scale preparation was developed in support of a drug development program at Merck Research Laboratories. The key steps include a tandem Heck-lactamization, N-oxidation, and a highly chemoselective Grignard addition of 4-(N-tert-butylpiperidinyl)magnesium chloride to a naphthyridone N-oxide. The N-oxide exerted complete chemoselectivity via chelation in directing the Grignard addition to the alpha position as opposed to 1,4-addition on the ene-lactam. The dihydropyridyl adduct was in situ aromatized with isobutylchloroformate followed by heating in pyridine. Syntheses of Grignard precursor, N-tert-butyl-4-chloro-piperidine, were accomplished via transamination with a quaternary ammonium piperidone or via addition of methylmagnesium chloride to an iminium ion. Utilizing this chemistry, multi-kilogram preparation of compound 1 was successfully demonstrated.

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