Isomerism diastereoisomers

N. Bodor and M. J. Huang, /. Comput. Chem., 12,1182 (1991). Predicting Partition Coefficients for Isomeric Diastereoisomers of Some Tripetide Analogs. 

Consider 7.53 and its enantiomer ent-7.53. These are clearly related as object and mirror image and, in the enantiomer, chiraUty, is reversed at each of the two asymmetric carbon atoms. What is the relationship between these two molecules and the enantiomeric pair 7.54 and ent-7.54 Remembering what we said about stereoisomers at the start of the chapter, the relationship between 7.53 and 7.54 is that of diastereoisomers—all relationships that are not enantiomeric are diastereo-isomeric. Diastereoisomers are different compounds, with different chemical and physical properties. Enantiomers have the same physical properties other than their ability to rotate the plane of plane-polarized light and the same chemical reactivity unless they are reacting with a chiral reagent. 

The l l-adducts obtained from the ethylene phosphonothioites (38 R = Ph or Bu ) with diacetyl, benzylideneacetylacetone, and phen-anthraquinone readily eliminate ethylene sulphide to give the corresponding phosphonate or phosphinate esters. The benzylideneacetylacetone adduct of (38 R = Bu ) contained the two diastereoisomers (39) and (40) which, on elimination of ethylene sulphide at 100 °C, gave isomeric phosphinates. 

The reaction was performed by heating the reagents at 150 °C for 10 h in o-xylene. The desired exo adduct was obtained with high stereoselectivity and subsequent formation of the diastereoisomer 58 was considered to occur by isomerization of the exo adduct. The reaction was dramatically accelerated by use of microwave irradiation in a domestic microwave oven, and the carboxylic acid was obtained after 45 min with a small increase in stereoselectivity (Scheme 9.15) [57]. 

Key steps are the enantioselective isomerization of diethylgeranylamine and the diastereoselective ring closure of (+)-citronellal to (—)-isopulegol. Mechanistically, the isomerization is well understood. As to the cyclization, notably, the most stable (all-equatorial) diastereoisomer is formed. 

Iodinated contrast agents with polyhydroxylated carbon side-chains contain a number of asymmetric carbon atoms yielding numerous optical isomers which relate to each other as enantiomers or diastereoisomers. Sterically hindered non-asymmetric carbon or nitrogen atoms might result in additional asymmetry centres while the partial double bond character of the acyl-carbon-nitrogen bond of amide functions can lead to cisitrans isomerism. Such isomers are labelled rotamers when heating in solution is able to modify their ratio. Isomerism of iodixanol has been described by Priebe et al. [122], Fossheim et al. [123] and by Molander et al. [115]. 

We have investigated the isomerism of iotrolan by HPLC in order to correlate the pattern of HPLC peaks with rotamers, groups of diastereoisomers or with individual diastereoisomers [124]. 

Two 4-methylene-l,3-dioxane diastereoisomers, isomeric at C-6, were subjected to the rhodium-catalyzed hydro-formylation. The stereochemistry of the newly formed stereogenic carbon was guided solely by the acetal stereocenter (not by C-6) (Scheme 56) <1997JA11118, 1998TL6423>. 

Grigg and co-workers (310) recently examined the 1,3-APT reaction of various aldoximes (270) (R or R = H) with divinyl ketone (Scheme 1.56). While ketoximes 270 (R = R) form a mixture of adducts, 271 and 272 via nitrone 273, the aldoximes selectively afford 272 (as a mixture of endo and exo diastereoisomers). Under the thermal reaction conditions, the oxime starting materials can undergo ( /Z) isomerization, while the nitrone intermediate was expected to be unaffected and the isolated cycloadducts showed no interconversion via cycloreversion. Thus, the increasing selectivity for endo-212 [via ( )-273, R = H] over exo-212 [via (Z)-273, R = H] with the increasing size of the aldoxime substituent was attributed primarily to the inhibition of oxime isomerization by steric clash between R or R and the oxime OH. In contrast, Lewis acid catalysis, in particular by hafnium (iv) chloride, of the cycloaddition of various aldoximes with this dipolarophile gave exo-271 exclusively (216). 

Me, R = OMe, in the presence of zinc or cadmium as the coordinating metal ion, led to the formation of 343 in 89% and 343 in 90% yield, respectively. While the zinc mediated reaction led to the formation of a single stereoisomer in 80% yield, for R = Ph, R = OMe, cadmium led to the formation of a 9 1 ratio of diastereoisomers, although it is unclear whether this difference in stereocontrol is due to change in the metal or subsequent product isomerization, due to prolonged reaction times and contact with Dowex resin (Scheme 3.116) (98). 

Diazo compounds also undergo cycloaddition with fullerenes [for reviews, see (104),(105)]. These reactions are HOMO(dipole)-LUMO(fullerene) controlled. The initial A -pyrazoline 42 can only be isolated from the reaction of diazomethane with [60]fullerene (106) (Scheme 8.12) or higher substituted derivatives of Ceo (107). Loss of N2 from the thermally labile 42 resulted in the formation of the 6,5-open 1,2-methanofullerene (43) (106). On the other hand, photolysis produced a 4 3 mixture of 43 and the 6,6-closed methanofullerene (44) (108). The three isomeric pyrazolines obtained from the reaction of [70]fullerene and diazomethane behaved analogously (109). With all other diazo compounds so far explored, no pyrazoline ring was isolated and instead the methanofullerenes were obtained directly. As a typical example, the reaction of Cgo with ethyl diazoacetate yielded a mixture of two 6,5-open diastereoisomers 45 and 46 as well as the 6,6-closed adduct 47 (110). In contrast to the parent compound 43, the ester-substituted structures 45 and 46, which are formed under kinetic control, could be thermally isomerized into 47. The fomation of multiple CPh2 adducts from the reaction of Ceo and diazodiphenylmethane was also observed (111). The mechanistic pathway that involves the extrusion of N2 from pyrazolino-fused [60]fullerenes has been investigated using theoretical methods (112). 

Rhodium-catalyzed hydroformylation of -(substituted amino)benzyl-amines (387, X = H2) and -(substituted amino)benzamides (387, R = H, X = O) in the presence of rhodium(II) acetate dimer and triphenylphos-phine in deoxygenated ethyl acetate gave a 7 3 mixture of 1,2,3,4,4 ,5-hexahydro-6//-pyrido[l,2-a]quinazolines (388, X = H2,0) and isomeric 3-methyl-l,2,3,3fl,4,5-hexahydropyrrolo[l,2-a]quinazolines (389, X = H2, O) (94AJC1061). The methyl derivative of benzylamine 387 (R = Me, X = H2) afforded a mixture of diastereoisomers 390 and 391 (X = H2). Their ratio depended on the reaction time. Longer reaction times gave more 391 (X = H2), containing the methyl group in an equatorial position. Compound 390 isomerized into 391 (X = H2), under the aforementioned conditions. The benzamide derivative (387, R = Me, X = O) yielded only one isomer (391, X = O), independent of the reaction period. 

The hetero-Diels-Alder reaction of activated butadienes with carbonyl compounds is a convenient method for the preparation of precursors of sugars. Up to three chiral centers are created simultaneously. The high-pressure [4 + 2]cycloaddition of l-methoxybuta-1,3-diene 32 to N-mono- and N,N-diprotected alaninals was investigated [42-45]. The Eu(fod)3-mediated reaction of 32 with alaninal 25 gave a mixture of four diastereoisomers, which was then subjected to acidic isomerization, leading to the thermodynamically more stable pair of adducts syn-33 and anti-34, with predominance of the latter isomer (Scheme 12). The N-monoprotected alaninals reacted with a moderate ryn-diastereoselectivity. This method was used in the synthesis of purpurosamines (see Sec. DI.C). 

Considerable ingenuity was required in both the synthesis of these chiral compounds695 697 and the stereochemical analysis of the products formed from them by enzymes.698 700 In one experiment the phospho group was transferred from chiral phenyl phosphate to a diol acceptor using E. coli alkaline phosphatase as a catalyst (Eq. 12-36). In this reaction transfer of the phospho group occurred without inversion. The chirality of the product was determined as follows. It was cyclized by a nonenzymatic in-line displacement to give equimolar ratios of three isomeric cyclic diesters. These were methylated with diazomethane to a mixture of three pairs of diastereoisomers triesters. These dia-stereoisomers were separated and the chirality was determined by a sophisticated mass spectrometric analysis.692 A simpler analysis employs 31P NMR spectroscopy and is illustrated in Fig. 12-22. Since alkaline phosphatase is relatively nonspecific, most phosphate esters produced by the action of phosphotransferases can have their phospho groups transferred without inversion to 1,2-propanediol and the chirality can be determined by this method. 

Support for these types of ylide isomerization may be drawn from the rearrangements seen in less stabilized ylides. Equation 23 shows a ring contraction related to the expansion reactions of equations (9)—(11) (8iJCS(Pl)l953). As in those examples, the stabilized ylide (79) requires heating to effect the reaction the product is a single diastereoisomer, derived from a predominantly endo pathway. 

The results in Table VIII show that the selectivity with Co2(CO)8, although higher than that obtained with l-phenyl-2-methylpropene, is still very low. The aldehyde distribution is comparable with that for methyl tiglate. The main isomeric aldehyde is 27, and the erythro and threo diastereoisomers are formed in the same proportions. With rhodium the selectivity is very high, and the main aldehydes are 26 and 27. Twice as much threo isomer as erythro isomer is produced (14.2 and 8.4% ). 

Z)-2-Phenyl-2-butene. (Z)-2-pheny 1-2-butene is not as stable as its (E) isomer. When Co >(CO)8 is used, results are the same with the (E) stereoisomer. However, when rhodium is used, isomer selectivity changes (Table VIII). The main isomeric aldehyde is the erythro di-astereoisomer which represents 33.9% of the whole mixture. Aldehyde 27 is formed in nearly the same ratio (32.9% ) while 6.8% and 4.4% of aldehyde 26 and the threo diastereoisomer are formed. 

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