Described herein is an efficient asymmetric synthesis of the potent antiarrhthymia agent The route is convergent and is highlighted by two stereoselective reactions. A rutheniumcatalyzed, enantioselective hydrogenation of an enamide was developed for the preparation of the key amine intermediate. Oxazaborolidine-mediated ketone reduction was utilized to establish the alcohol stereochemistry. Optimization of this chemistry led to an IPA modified reduction method which provides enhanced stereoselectivity.

Chiral Michael additions of methyl vinyl ketone (MVK) to indanone 2-carboxylic esters are well precedented in the literature.1 However, many of these methods are not applicable to 2-alkylindanones such as 1, containing a proton less acidic than the /3-keto ester.2 Here we report j.®-a an addition of MVK to indanone 1 catalyzed by the quaternary salts of Cinchona alkaloids in 95% yield and up to 80% enantiomeric excess (ee). This chiral Michael addition,3 followed by aldol condensation to complete the Robinson annelation, was the key step in our preparation of drug candidate 3.4 Cinchona alkaloids are not basic enough to catalyze Michael additions to the 2-propylindanone 1. Wynberg reportslb that the corresponding quaternary salts are not as effective as catalysts as the free bases.5 However, excellent results have been obtained in these laboratories in phase-transfer alkylations with quaternary Cinchona alkaloid catalysts6 leading to a synthesis of 3 employing

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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 ...

A combined chemical/chiroptical microscale protocol for the determination of absolute configurations of cyclic alpha-hydroxyketones is described. The hydroxyl group in cyclic alpha-hydroxyketones is converted into (3-aminopropylamino)acetate (NH2CH2CH2CH2NHCH2COOR), or more generally, according to a newly developed protocol, into (3-hydroxypropylamino)acetate group (HOCH2CH2CH2NHCH2COOR). The resultant conjugated compound forms a 1:1 host-guest complex with a dimeric zinc porphyrin tweezer, which exhibits exciton-coupled bisignate CD spectrum centered around the 420-nm porphyrin Soret band due to induced helicity between the two porphyrins in the complex. The absolute configurations of the alpha-stereogenic center is then determined by comparison of the sign of the observed CD exciton couplet of the complex with that of the preferred porphyrin twist predicted by the Merck Molecular Force Field (MMFFs) method.