Diastereomeric hydrazones

B. 5-Hexynal. To a solution of 5.60 g. (0.050 mole) of 2,3-epoxycyclohexanone in 120 ml. of benzene in a 500-ml. round-bottomed flask is added 10.82 g. (0.051 mole) of trans-1 -amino-2,3 diphenylaziri-dine.2 Initially, after brief swirling at room temperature, the reaction mixture is a colorless, homogeneous solution however it rapidly turns yellow and cloudy due to separation of water. After 2 hours the benzene and water are removed as an azeotrope under reduced pressure on a rotary evaporator with the bath maintained at approximately 30°. The resulting crude mixture of diastereomeric hydrazones weighs 15.4 g. (Note 7) and is subjected directly to the fragmentation reaction (Note 8). 

Most resolution is done on carboxylic acids and often, when a molecule does not contain a carboxyl group, it is converted to a carboxylic acid before resolution is attempted. However, the principle of conversion to diastereomers is not confined to carboxylic acids, and other groupsmay serve as handles to be coupled to an optically active reagent. Racemic bases can be converted to diastereomeric salts with active acids. Alcohols can be converted to diastereomeric esters, aldehydes to diastereomeric hydrazones, and so on. Even hydrocarbons can be converted to diastereomeric inclusion... 

Initial applications of SAMP and RAMP hydrazones in regio- and enantio-specific aldol reactions were first reported by Enders group. In these initial studies, several methyl ketones were converted into SAMP hydrazones, deprotonated with Bu Li and then allowed to react with various aldehydes and methyl ketones. The diastereomeric hydrazone products of these reactions were then cleaved to form 3-ketols in good chemical yields and with enantiomeric excesses of 31-62%. 

Halpem [8] described the reaction of cyclic ketones containing an asymmetric carbon a to the carbonyl function with (- -)-2,2,2-trifluoro-l-phenylethylhydra-zine (47) (see Section 4.4.2 for structures of numbered reagents) to form diastereomeric hydrazones, which were resolved by GC. However, some racemization was noted and it was recommended that the reaction should not be considered for ketones containing a hydrogen a to the asymmetric carbon. The enantiomers of cyclic ketones have also been separated as diastereomeric oximes by Pappo [114] in this reaction the racemic ketone was treated with R-2-amino-oxy-4-methylvaleric acid (48) in methanol/pyridine (10 1) at room temperature for 18 h. The diastereomers were separated on silica... 

Chromatography Pereira et al. [122] separated a range of cyclic ketones and steroids as their diastereomeric hydrazones using an OV-17 column at temperatures between 140 and 280 °C. 

Just like with all of the other reactions we have seen in this section, we need to take special notice of whether or not the starting ketone is symmetrical. If the starting ketone is unsymmetrical, then we should expect to form two diastereomeric hydrazones ... 

The use of hydrazone or enamine derivatives of ketones or aldehydes offers the advantage of stcreocontrol via chelated azaenolates. Extremely useful synthetic methodology, with consistently high anti selectivity, has been developed using azaenolates based on (S)- or (R)-l-amino-2-(methoxymethyl)pyrrolidine (SAMP or RAMP)51 58 (Enders method, see Section 1.5.2.4.2.2.3.). An example which illustrates the efficiency of this type of Michael addition is the addition of the lithium azaenolate of (5 )-l-amino-2-(methoxymethyl)pyrrolidine (SAMP) hydrazone of propanal (R = II) to methyl (E )-2-butenoate to give the nub-isomer (an 1 adduct) in 80% yield with a diastereomeric ratio > 98 2,... 

It is assumed that the reaction is initiated by a radical bromine abstraction to give 10-13, which after carbon monoxide insertion undergoes a rapid 5 -exo cycliza-tion onto the hydrazone moiety. The two diastereomeric hydrazinyl cyclopentanones 10-16 and 10-17 are formed with good yields, though with low stereoselectivity. 

Dihydrooxadiazoles 106 have been syntheised in moderate to high diastereomeric excess by the addition of aromatic nitrile oxides across the C=N bond of the hydrazones 105. The N-N bond can subsequently be cleaved with formic acid, and the chiral auxiliary recycled <99H(50)995>. The oxadiazolone 108 was produced (56%) from the oxime 107 by heating it with phenyl isocyanate <99SC3889>. ... 

Lanthanide shift reagents have been used to differentiate diastereomeric oximes, dinitrophenyl-hydrazones 304,305, and nitrones 306. A collision complex model to rationalize aromatic solvent induced shifts in the spectra of oximes and hydrazones has been developed305,307. 

Since the above cleavage methods proceed without racemization, the enantiomeric excess of the alkylated carbonyl compounds obtained can be safely determined by measuring the diastereomer-ic ratio of the alkylated hydrazones (see Section I.I.I.4.2.3.). The diastereomeric excess of SAMP-hydrazones derived from aldehydes was further determined by gas chromatography41. 

In addition, alkylated aldehydes can be transformed to (—)-(5)-l-amino-2-(tcr/-butyldi-methylsilyloxymethyl)pyrrolidine (SASP)-hydrazones without racemization. The diastereomeric ratio of these hydrazones can be determined directly using HPLC. Furthermore, this method allows determination of the absolute configuration of the alkylated hydrazones, since SASP-hy-drazones of (S, -configuration always elute first11 25. 

An alternative access was achieved by alkylation of the a-diphenylphosphino acetaldehyde SAMP hydrazone 95, yielding the hydrazone products 96 in good yields (60-63%) and good diastereomeric excesses (die = 68-71%) as EjZ mixtures, from which the major diastereomer was separated and purified by preparative HPLC. Ozonolysis and in-situ reduction with the borane-dimethyl sulfide complex of the aldehydes generated gave the air-stable borane-protected 2-diphenylphosphino alcohols 97 in good yields (67-83%). Reaction with DABCO afforded the unprotected 2-phosphino alcohols 98 in very good yields (85-91%) and excellent enantiomeric excesses (ee > 96%) (Scheme 1.1.27). 

The methyl group was introduced by a two-step procedure. Thus, the hydrazone Michael adducts 52 were converted into the enol pivaloates 53 in excellent yields and diastereomeric excesses de > 96%) by treatment with pivaloyl chloride and triethylamine. After treatment with lithium dimethylcuprate the chiral auxiliary was removed by addition of 6n HCl in order to obtain the 5-substituted 2-methylcyclopentene carboxylate 54 in good yields and with excellent stereoselectivity (de, ee > 96%). Finally, the asymmetric synthesis of dehydroiridodiol (55, R = Me, = H) and its analogues was accomplished by reduction of 54 with lithium aluminum hydride or L-selectride leading to the desired products in excellent yields, diastereo- and enantiomeric excesses (de, ee > 96%). 

Having the electrophile 95 to hand, the synthesis proceeded by metallation of the SAMP hydrazone 96 followed by alkylation with the iodide affording the a-alkylated hydrazone 97 with diastereomeric excess de = 9S% (Scheme 1.2.21). The removal of the auxiliary proceeded smoothly with oxalic acid, leading to 98 in good yield (80%, two steps) and no epimerization without deprotection of the amino group. 

As is depicted in Scheme 1.2.29, the epoxide 128 was synthesized starting from 2,2-dimethyl-l,3-dioxan-5-one RAMP hydrazone (R)-96, which was double-alkylated with methyl iodide at a- and a -positions leading to the trons-dimethylated hydrazone 131 in 79% yield over two steps and excellent stereoselectivity (de, ee > 96%) [68]. The quaternary stereocenter bearing the desired tertiary alcohol function was generated using benzyloxymethyl chloride (BOMCl) as the electrophile to trap the lithiated hydrazone 131, providing the a-quaternary hydrazone 132 in very good yield (92%), excellent diastereomeric and enantiomeric excesses (de, ee > 96%) and with the required cis relationship of the methyl substituents. 

The mixture of the crude product hydrazone 138 and the excess of hydrazone 129 was used directly in an acidic acetalization reaction utilizing aqueous 3n HCl in a biphasic system and gave a diastereomeric mixture of sordidin (126) and 7-epi-sordidin (7-epi-126) in 84% yield over two steps in a 1.5 1 ratio. Gratifyingly, we succeeded in separating the desired sordidin epimers by preparative gas chromatography. As a result, both could be obtained in diasteromerically pure form (sordidin de > 99% 7-epi-sordidin de > 97%) and with a high enantiomeric excess for each epimer (ee > 98%). 

Hydrazones have also been used as azomethine imine precursors to achieve cycloadditions.157 Proto-nated hydrazones act under suitable conditions as quasi-azomethine imines in polar [3+ + 2] cycloadditions. Thus, r.cetaldehyde phenylhydrazone (201) was found to react with styrene in the presence of sulfuric acid in a regiospecific manner to give pyrazolidine (203 Scheme 47) as a diastereomeric mixture.157 The most commonly used azomethine imine has a phenyl group attached to one end of the dipole and hence has a raised HOMO relative to the unsubstituted system. Because the coefficients at the terminal atoms of the dipole are smaller in the LUMO than they are in the HOMO, the phenyl group does not lower the energy of the LUMO as much as it raises the energy of the HOMO. With electron-deficient di-polarophiles like methyl acrylate, the reaction is dipole HOMO-controlled, and mixtures can be expected. In fact, a 1 1 mixture of regioisomers was obtained in the reaction of (201) with acrylonitrile (equation 9).157... 

Acylated 2-aminopyrazole 1-oxides 118 were prepared in excellent yields by heating (5-nitroacylhydrazones 117 to reflux with sodium methoxide in methanol (2006SL2731). The nitroacylhydrazones 117 were synthesized by treatment of 2-diaza-l,3-butadienes 115 with nitroalkanes 116 and catalytic amounts of sodium methoxide under solvent-free conditions at room temperature. The nitroalkane anion adds to the hydrazone 115 in a conjugated fashion producing diastereomeric mixtures of nitroac-ylhydrazone 117 in high yields (Scheme 36). 

The main and trace products are diastereoisomers, which can be completely separated by using chromatography. The separation affords a diastereomerically and enantiomerically pure SAMP hydrazone E. 

Asymmetric synthesis (1) Use a chiral auxiliary (chiral acetal—the synthetic equivalent of an aldehyde chiral hydrazone—the synthetic equivalent of a ketone) covalently attached to an achiral substrate to control subsequent bond formations. The auxiliary is later disconnected and recovered, if possible. (2) Use a chiral reagent to distinguish between enantiotopic faces or groups (asymmetric induction) to mediate formation of a chiral product. The substrate and reagent combine to form diastereomeric transition states. (3) Use a chiral catalyst to discriminate enantiotopic groups or faces in diastereomeric transition states but only using catalytic amounts of a chiral species. 

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