Frans-Diastereomer

The first two principles were successfully applied by Scott et al. for the preparation of tri- and tetra-ferf-butylphospha[3]- and -[4]pericyclines 67 and 68, respectively (Scheme 13) [19]. While 67 was obtained as a single compound, the frans-diastereomer, the tetraphospha[4]pericycline 68 was obtained as a mixture of four diastereomers. 

Eventually, the same method was applied to the dihydroisoquinoline derivative 135 g, and the hexahydropyrroloisoquinoline 141 was isolated in 78% yield (with a 1.8 1 ratio of cis- and frans-diastereomers) (Scheme 45) [60b]. 

Introduction of the C2 sulfonamide is accomplished via sulfonylation with chlorosulfonic acid, conversion to the sulfonyl chloride using thionyl chloride, and amidation using concentrated ammonium hydroxide in tetrahydrofuran. Reduction of the 4-acetamido compound using borane-tetrahydrofuran complex provides the 4-ethylamino derivative. The 45,65-frans diastereomer is selectively crystallized as its maleate salt from acetone in the presence of the unwanted 4R,6S-cis diastereomer. Neutralization of the maleate salt and extraction of the free base in ethyl acetate, followed by formation of the hydrochloride salt, yields crude dorzolamide hydrochloride. 

They have employed the strategy of intramolecular trans alkylation of azetidin-2-ones since C-4 substituted azetidin-2-one enolates, predominantly yield the C-3, 4-frans-diastereomer upon reaction with electrophiles, [45] thus, providing control of stereochemistry of substituents at the cyclohexyl ring (Scheme 25). 

The stereoselective reduction of meso-bis(bicyclopropylidenyl) (meso-87) with lithium in liquid ammonia gave an almost quantitative yield of the two dia-stereomeric quatercyclopropyls trans,trans-229 and cis,trans-230 in a ratio of 4.4 1 (Scheme 53) [56]. On the other hand, reduction of meso-87 with diimine generated from 2-nitrobenzenesulfonyl hydrazide gave the cis,cis-quatercyclo-propyl (231) (Fig. 6) as the main product (isolated by chromatography) along with the ds,frans-diastereomer 230 (Scheme 53) [56]. 

An effect of high pressure on the diastereoselectivity is also observed for intramolecular hetero Diels-Alder reactions as found for the cycloaddition of the benzylidene-isoxazolone 8-23 to afford the cis-annulated 8-24 as the major product together with the frans-diastereomer 8-25 (Fig. 8-8) [549], However, the difference in activation volume with AAV =1.6 0.2 cm3 mol"1 is rather small. The activation volume with AV = 19.6 0.5 cm3 mol-1 at 343 K lies significantly below the usual values found for intermolecular cycloadditions of 1-oxa-1,3-butadienes, indicating that this reaction may be on the border line to a two-step reaction but see also below. 

While the syntheses of the acyclic precursors in the examples above each require a couple of steps, symmetrical dienynes with a central triple bond and heteroatoms in the tethers are more easily accessible. They can yield heterotricyclic compounds by the same reaction mode, for example, the diaza- and dioxatricycles 121 are obtained starting from dienynes 119 (Scheme 18) [73]. Yields were best (90%) with N-tosyl linkers, with N-Boc groups the reaction was slower (41% yield), and with N-benzyl linkers only decomposition occurred. This may be due to coordination and blocking of the catalyst by the more Lewis-basic amines. The cis- and frans-diastereomers of 121 were formed in a ratio of 1.8 1, and this ratio did not change in other solvents, at different temperatures, with other catalyst precursors or under high pressure (10 kbar). In view of the apparent influence of the tether, the unsymmetrical oxazaprecursor 122 gave a 7 3 mixture of tricycles 123 and 124. Obviously, the hydridopalladation of the triple bond occurred with some regioselectivity such that intramolecular carbopalladation of the allyl-amine predominated. It is noteworthy that in these cases the intramolecular Diels-Alder reactions of the intermediate trienes 120 already occur under the employed conditions, i.e. at 80 °C. 

Both enantiomers of the c/s-diastereomer are of equal stability as are both enantiomers of the frans-diastereomer. The frans-diastereomer is more stable than the c/s-diastereomer because it has the conformation with both substituents equatorial. The methyl group is axial in the more stable conformer of the less stable diastereomer (cis) because the axial strain energy of the phenyl group is larger than that of the methyl group. 

The reaction of a linear aliphatic-substituted homoaldol illustrates an interesting feature of this kinetic resolution (Scheme 14). As an additional acetal stereocenter is created in the transacetalization reaction, the high catalyst control of its formation results in ahighly diastereoselective reaction [26, 35, 36]. Thus, even in cases where the enantiodifferentiation of the starting material is not very pronounced, the less reactive enantiomer is converted into the minor frans-diastereomer (Scheme 14). 

Similarly, a 1 1 mixture of diastereomers is the result of methylation of the frans-disubstituted -lactone 354... 

Dauben s group utilized the same retrosynthetic disconnections, but chose to add more functionality to the cycloaddition precursor. From a simple frans-disubstituted cyclopentane, Dauben used an aldol reaction of a cyclopropylvinyl aldehyde to prepare the cycloaddition precursor. The diazo-substituted p-ketoester was completed using a Roskamp-Padwa coupling followed by diazo-transfer. Addition of rhodium acetate to the diazo substituted p-ketoester 179 led to an excellent 86% yield of the correct diastereomer (Scheme 4.42). 

Chiral-trans-l,2-disubstituted-l,2-dihydronaphthalenes (cf. 12, 310-311).1 Addition of an organolithium to chiral (l-naphthalyl)oxazolines (2, derived from 1) followed by quenching with CF3COOH results in the salt 3. This product is reduced by LiAlH4 to a single frans-l,2-diaxial diastereomer 4. 

We have seen that enantiomers have identical physical properties except for the direction in which they rotate polarized light. Diastereomers, on the other hand, generally have different physical properties. For example, consider the diastereomers of but-2-ene (shown next). The symmetry of zram -but-2-ene causes the dipole moments of the bonds to cancel. The dipole moments in cw-but-2-ene do not cancel but add together to create a molecular dipole moment. The dipole-dipole attractions of d.y-but-2-enc give it a higher boiling point than fran.y-but-2-ene. 

For example, syn dihydroxylation of frans-crotonic acid gives the two enantiomers of the threo diastereomer of 2,3-dihydroxybutanoic acid. The same reaction with m-crotonic acid gives the erythro diastereomer of the product. 

Whenever the two groups on each end of a C = C are different from each other, two diastereomers are possibie. C/s- and frans-2-butene (drawn at the bottom of Tabie 10.1) are diastereomers (Section 8.2B). 

---