Resolution Ring-forming reactions

Carbodiimides have chiral structures similar to allenes, i.e., they can exist in optically active forms. Schloegl and Mechtler were the first to report a partial optical separation of N,N"-diferrocenylcarbodiimide into enantiomers by chromatography on acetylated cellulose, but other authors doubt the validity of these results. According to theoretical calculations a separation of carbodiimide enantiomers is not possible. N,N -diferrocenylcarbodiimide was also obtained in optically active form by kinetic resolution in the reaction with (-)-S-6,6"-dinitrodiphenic acid. Cervinka and coworkers isolated both enantiomers of (R,S)-N,N"-bis(o -phenylethyl)carbodiimide, and they found that they undergo racemization at room temperature. A recent study on the racemization mechanism of macrocyclic carbodiimides indicates that the open chain as well as the large ring carbodiimides racemize by nitrogen inversion or tra 5-rotation, while medium size cyclic carbodiimides racemize by cw-rotation. ... 

Using monofunctional model compounds, Fyfe et al. recently studied the reaction by high resolution 1H-, 13C-, and 15N-NMR spectroscopy and mass spectroscopy [178]. The major cross reaction product is a racemic mixture of enantiomers containing an oxazolidinone ring formed from one cyanate and two epoxy molecules. Epoxy consumption lags behind the cyanate consumption as triazine formation is faster than both the self-polymerization of epoxy and cy-... 

The kinetic resolution should be considerably enhanced if a chiral dicar-boxylic acid capable of ring formation to both 6-hydroxy groups of skyrin would be applied. We selected for this purpose 6,6 -dinitrodiphenic acid dichloride (32) which can easily be obtained in both enantiomeric forms. Reaction of (+)-(R)-binaphthol 31 with racemic 32 afforded the (+)-lactone 33, [a]p +213°, whereas the unreacted acid 34 showed a negative rotation (Scheme 7). Further investigations with the optically pure reagents indicated that (+)-(R)-31 forms only a lactone 33 with (+)-(R)-32 whereas (-)-( )-31 reacts only with (-)-( )-32. The same results were obtained with tetrachlorodiphenic acid dichloride. Similar observations have recently been published by Miyano and co-workers (ref. 20) for 1,1 -binaphthyl-2,2 -dicarboxylic dichloride. 

Schemes 3-7 describe the synthesis of cyanobromide 6, the A-D sector of vitamin Bi2. The synthesis commences with an alkylation of the magnesium salt of methoxydimethylindole 28 to give intermediate 29 (see Scheme 3a). The stereocenter created in this step plays a central role in directing the stereochemical course of the next reaction. Thus, exposure of 29 to methanol in the presence of BF3 and HgO results in the formation of tricyclic ketone 22 presumably through the intermediacy of the derived methyl enol ether 30. It is instructive to point out that the five-membered nitrogen-containing ring in 22, with its two adjacent methyl-bearing stereocenters, is destined to become ring A of vitamin Bi2. A classical resolution of racemic 22 with a-phenylethylisocyanate (31) furnishes tricyclic ketone 22 in enantiomerically pure form via diaster-eomer 32.

Alternatively, epoxides can be formed with concomitant formation of a C-C bond. Reactions between aldehydes and various carbon nucleophiles are an efficient route to epoxides, although the cis. trans selectivity can be problematic (see Section 9.1.4). Kinetic resolution (see Section 9.1.5.2) or dihydroxylation with sequential ring-closure to epoxides (see Section 9.1.1.3) can be employed when asymmetric epoxidation methods are unsatisfactory. 

An interesting extension of this reaction is shown in the asymmetric kinetic resolution of cyclic allylic ether 44 under alkene coupling conditions. Use of (R)-12 as the catalyst gives (R)-45 in > 99% ee at 58% conversion. The ethylated product 46 is also formed in the reaction in 94% ee (Eq. 7) [25]. The reaction is effective for six- to eight-membered 3-oxacycloalkenes 47 as well as for a wide variety of alkoxycycloalkenes 48 [27], with some resolution dependency on the ring size of 47 (Fig. 2) [26]. 

Use of the relatively small cyclopropane ring drastically reduces the potential for deleterious steric bulk effects and adds only a relatively small lipophilic increment to the partition coefficient of the drug. One of the clever elements of the rolicyprine synthesis itself is the reaction of d,l tranylcypromine (67) with L-5-pyrrolidone-2-carboxylic acid (derived from glutamic acid) to form a highly crystalline diastereomeric salt, thereby effecting resolution. Addition of dicyclohexylcarbodiimide activates the carboxyl group to nucleophilic attack by the primary amine thus forming the amide rolicyprine (68). 

Molybdenum catalysts that contain enantiomerically pure diolates are prime targets for asymmetric RCM (ARCM). Enantiomerically pure molybdenum catalysts have been prepared that contain a tartrate-based diolate [86], a binaph-tholate [87], or a diolate derived from a traris-1,2-disubstituted cyclopentane [89, 90], as mentioned in an earlier section. A catalyst that contains the diolate derived from a traris-1,2-disubstituted cyclopentane has been employed in an attempt to form cyclic alkenes asymmetrically via kinetic resolution (inter alia) of substrates A and B (Eqs. 45,46) where OR is acetate or a siloxide [89,90]. Reactions taken to -50% consumption yielded unreacted substrate that had an ee between 20% and 40%. When A (OR=acetate) was taken to 90% conversion, the ee of residual A was 84%. The relatively low enantioselectivity might be ascribed to the slow interconversion of syn and anti rotamers of the intermediates or to the relatively floppy nature of the diolate that forms a pseudo nine-membered ring containing the metal. 

Asymmetric Synthesis Using a Chiral Molybdenum Catalyst In olefin metathesis, a double bond is cleaved and a double bond is formed. Thus, a chiral carbon center is not constructed in the reaction. To realize the asymmetric induction by ring-closing metathesis, there are two procedures a kinetic resolution and desym-metrization of symmetric prochiral triene. Various molybdenum complexes are synthesized in order to explore the viabihty of these approaches (Figure 6.2). 

An efficient and simple kinetic resolution of the racemic Betti base 387 was achieved via its reaction with acetone in the presence of L-(- -)-tartaric acid. When a suspension of racemic 387 in acetone was treated with L-(- -)-tartaric acid, the (A)-enantiomer formed a crystalline L-tartrate salt 389 this was filtered off, and the (iJ)-enantiomer could be isolated as a naphth[l,2-< ]oxazine derivative 388 from the filtrate (Equation 41). Both enantiomers were obtained in excellent yields and ee s. The enantioseparation is presumed to take place via a kinetically controlled N,0-deketalization of the (3)-naphth[l,2-< ]oxazine derivative <2005JOC8617>. An improved method for the enantioseparation of 387 was developed by the reaction of the ring-chain tautomeric l,3-diphenyl-3,4-dihydro-2//-naphth[2,l-< ][l,3]oxazine (41 X, Y = H) and L-(-f)-tartaric acid, yielding the crystalline 389 in 85% yield <2007SL488>. 

The kinetic resolution of racemic l-(benzofuran-2-yl)ethanol rac-33 having different substituents on the benzene was reported ring using lipase-catalyzed transesterification with vinyl acetate as acyl donor. The reaction afforded (lA)-l-acetoxy-l-(benzofuran-2-yl)ethanes (A)-34 and (16)-l-benzofuran-2-yl)ethanols (S)-33 in highly enantiopure form.65... 

This possibility of intimate association of rhodium with the aromatic ring suggests further experiments. A logical extension of asymmetric syntheses involving prochir-al reactants is a kinetic resolution with related chiral reactants under similar conditions. In the one case of hydroboration-amination where this has been applied, it has proved to be very effective. The reactant was prepared directly by a Heck reaction on 1,2-dihydronaphthalene, and under the standard conditions of catalytic hydrobora-tion gave >45% of both enantiomerically pure recovered alkene with (after oxidative work-up) the alcohol of opposite hand, mainly as the trans-isomer. This procedure forms a simple and potentially useful route to pharmacologically active substances, demonstrated by the racemic synthesis shown [105] (Scheme 34). 

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