SAMP hydrazone

Chiral hydrazones for asymmetric alkylations (RAMP/SAMP hydrazones- D. Enders "Asymmetric Synthesis" vol 3, chapt 4, Academic Press 1983)... 

MMPP-6H20 (magnesium monoperoxyphthalate), pH 7 buffer, MeOH, 0°, 5-120 min, 76-99% yield. These conditions were used to cleave the related SAMP hydrazone in the presence of two trisubstitued alkenes in 46% yield. ... 

J Based on polarimctry. NMR and GC analysis. These results support a uniform stereochemical course of the reaction The nucleophile attacks the Re-face of the SAMP-hydrazone. b Obtained with RAMP (2c) as auxiliary. 

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,... 

Thus, the lithiated SAMP hydrazones of various methyl ketones on addition to 2-(aryl-methylene)- , 3-propanedionates and propanedinitriles provide, after the removal of the auxiliary, (R)-2-( l-aryl-3-oxobutyl)-1,3-propanedioates and -propanedinitriles with high enantiomeric excess (> 95%) in 50 82% yield (sec Table 6) 195,197. Using similar methods optically active (5-lactones (90% to > 96% ee) are obtained198. 

The addition of the lithium azaenolate of the SAMP hydrazone of propanal to methyl (E)-2-butenoate to furnish the (S,S,S)-adduct in 58% yield with > 96% ee and de is illustrative for the efficiency of this asymmetric Michael addition10°. Only the anti-isomer (an / adduct) is found. This methodology was used in the synthesis of pheromones of the small forest and red wood ant200. 

Fig. 1.7. Crystal structure of lithium salt of SAMP hydrazone of 2-acetylnaphthalene. Two molecules of THF are present. Reproduced from Angew. Chem. Int. Ed. Engl., 27, 1522 (1988), by permission of Wiley-VCH.

An unusual temperature dependence on the regioselective behavior of an allylbarium species has been demonstrated in asymmetric allylation with the optically active imine SAMP-hydrazone [SAMP = (A)-(—)-l-amino-2-meth-oxymethylpyrrolidine] (Scheme 10).322 Its reaction with prenylbarium chloride at 0°C produced an a-allylated hydrazine in 60% diastereotopic excess, but at — 78 °C, the y-adduct was generated with 98% diastereotopic excess. The temperature dependence of the ct/y ratio may reflect competition between a kinetically favored y-adduct at low temperature and a thermodynamically preferred ct-form at higher temperatures. 

A good example of applying the hydrazone method is the preparation of the optically active pheromone 34 (Scheme 2-22).38 Further study of the crude product prepared from SAMP-hydrazone and 3-pentanone 33 shows that, among the four possible stereoisomers, (Z,S, S )-isomer 35 predominates along with the minor (E,S,S)-isomer, the geometric isomer of 35. The final product 34 was obtained with over 97% enantiomeric excess (ee). 

It has been reported that the cleavage of SAMP hydrazones can proceed smoothly with a saturated aqueous oxalic acid, and this allows the efficient recovery of the expensive and acid-sensitive chiral auxiliaries SAMP and RAMP. No racemization of the chiral ketones occurs during the weak acid oxalic acid treatment, so this method is essential for compounds sensitive to oxidative cleavage.393... 

Another application of the hydrazone method is the preparation of achy dr oxy carbonyl compounds (R4 = H in 37). The aldehydes/ketones 36 are first transformed into their corresponding SAMP-hydrazones 38, followed by deprotonation with f-butyllithium or LDA in THF. The resulting anion undergoes facile oxidation by treatment with 2-phenylsulfonyl-3-phenyloxaziridine (39), and the product can be obtained with good to excellent enantioselectivity (Scheme 2-23).39b... 

Enantioselective a-hydroxylotion of carbonyl compounds. The lithium enolates of the SAMP-hydrazones of ketones undergo facile and diastereoselective oxidation with 2-phenylsulfonyl-3-phenyloxaziridine (13, 23-24) to provide, after ozonolysis, (R)-a-hydroxy ketones in about 95% ee. High enantioselectivity in hydroxylation of aldehydes requires a more demanding side chain on the pyrrolidine ring such as —QCjHOjOCH, which also results in reversal of the configuration. 

Enantioselective synthesis of R R2CHNH2.1 Alkyllithiums add stereoselec-tively to the C=N bond of SAMP hydrazones (2) of aldehydes. Reductive cleavage of the N—N bond of the products (3) affords either (R)- or (S)-4 with recovery of... 

The addition of a-lithiomethoxyallene 144 [55] to benzaldehyde dimethylhydra-zone 145 (Eq. 13.48) leads to a mixture of pyrroline 146 and dihydroazete 147 [56]. The cydization in this case, which takes place in the same operation as the addition to the hydrazone, follows two distinct pathways, with attack of the nitrogen atom taking place at the inner, in addition to the terminal, carbon atom of the allene. A similar reaction of 144 with SAMP-hydrazone 148 (Eq. 13.49) leads to 3-pyrroline 149 in 88% yield and excellent diastereoselectivity [57]. Cleavage of the chiral auxiliary group from 149 takes place in two steps (1, methyl chloroformate 2, Raney nickel, 50 bar, 50 °C) in 74% overall yield. When the addition of 144 to 148 is conducted in diethyl ether, cydization of the adduct does not take place. Surprisingly, the hydrazones of aliphatic aldehydes react with 144 in poor yield in THF, but react quantitatively and diastereoselectively in diethyl ether to give the (uncyclized) allenyl hydrazone products. 

Equation 13.58 describes the radical cyclization of SAMP hydrazone 173 [67]. In the presence of tributyltin hydride and a radical initiator, cyclization to 174 takes place in 78% yield. It is not clear what the full scope of this reaction is or what its utility in synthesis might be. 

The metalation and alkylation of SAMP-hydrazones proceeds in analogy to the optimum deprotonation conditions developed for the corresponding dimethylhydrazones35. 

The ratio of diastereomers of the crude or purified SAMP-hydrazones can be measured by H-NMR shift experiments5. For example, using tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato)europium [Eu(fod)3] or tris[3-(heptafluorobutanoyl)-(1 / )-camphorato]europium [Eu(hfc)3] as shift reagent, the sharp methoxy singlet at 3.2 3.4 ppm is shifted to lower field by about 1 to 4 ppm, which allows the determination of each diastereomer present. 

A solution of 1.05 equiv of butyllithium in hexane (1.6 M) are added dropwise via syringe to a solution of 1.05 equiv of diisopropylaminc in diethyl ether (0.25-0.5 M) under argon at O C and stirred for 15 min lo generate a solution of 1.05 equiv of lithium diisopropylamide. After dropwise addition of 1.0 equiv of the SAMP-hydrazone, the mixture is stirred at 0 °C for 4 h, cooled to — 110 °C, and 1.05 equiv of the electrophile... 

The SAMP-hydrazone derived from 2,2-dimethyl-l,3-dioxan-5-one is used as a chiral 1,3-di-hydroxy-2-propanone enolate equivalent and transformed to the corresponding 4-alkyl derivatives in good yield and high enantiomeric purity (89 to >95% ee, see Table 2)15. 

Regioselectivity is not a problem in the metalation and alkylation of SAMP-hydrazones derived from aldehydes, symmetrical ketones and unsymmetrical ketones having one substituent without a-hydrogens. On the other hand, SAMP-hydrazones of unsymmetrical ketones react regioselectively at the less substituted carbon, regardless of the E/Z ratio of the starting hydrazone33. 

Exceptions are the SAMP-hydrazones derived from 2-phenylcycloheptanone8 and 1-phenyl-2-propanone3 where regioselectivity was incomplete (1 1 and 9 1, respectively). 

Alkylations of the SAMP-hydrazones of 2-cyclohexenone9-10 and 3-methylcyclohexanone8 occur exclusively at the 6-position. 

Due to the unique SE2 -front alkylation of metalated SAMP-hydrazones, the absolute configuration of the alkylation products is determined by the geometry of the azaenolate C—C double bond. Thus a uniform C—C geometry is essential in order to achieve high enantiomeric purities. 

Alkylation of the metalated SAMP-hydrazone derived from 3-pentanone showed no significant dependency of asymmetric induction on the azaenolate counterion8. 

The stereoselectivity of deprotonation is dependent on the solvent. Thus, the lithiated SAMP-hydrazone of propanal, which is generated in tetrahydrofuran, shows Ecc-Zcs configuration in >98% stereoselectivity. On the other hand, deprotonation in tetrahydrofuran/hex-amethylphosphoric triamide leads to a species with the opposite Zee cN configuration in >95% stereoselectivity. Alkylation of these azaenolates provides products of opposite absolute configuration23. 

In the case of alkylated SAMP-hydrazones derived from aldehydes, only two stereoisomers are observed, i.e., the (S,R)-(E)- and the (S,S)-( )-isomers. During H-NMR measurements of alkylated SAMP-hydrazones derived from ketones, a slow isomerization of the (S,R)-(Z)- and (5,S)-(Z)-isomers, generated during metalation, to the thermodynamically more stable (SJi)-(E)- and (S,5)-( )-isomers occurs3. 

Alkylations of SAMP-hydrazones derived from open chain and cyclic p-oxo esters proceed in good overall chemical yields, however, enantiomeric purities are relatively low (18-60% ee)8. 

After use of this cleavage method, the chiral auxiliary may be partially recycled by neutralization and extraction of the aqueous layer. In this way a mixture of methylated hydrazine, the SAMP-hydrazone of formaldehyde and SAMP (1 7 2) is obtained, which is subjected to air oxidation and hydrolysis8. 

A general oxidative cleavage reaction of ketone-derived SAMP-hydrazones can be realized without racemization by reaction with magnesium monoperoxyphthalate (MMPP) hexahydrate in methanol or in methanol/pH 7 phosphate buffer within 2 hours26. 

Alkylated Ketones by Cleavage of Alkylated SAMP-Hydrazones General Procedure for Oxidation with Magnesium Monoperoxyphthalate Hexahydrate2 ... 

SAMP-Hydrazones derived from ketones may also be cleaved by treatment with three equivalents of sodium perborate tetrahydrate at pH 7 in water/rert-butyl alcohol at 60 °C. Hydrolysis of aliphatic derivatives is effected in 4-24 hours and reactions yielding aromatic ketones proceed within 2- 3 days. This cleavage reaction furnishes the desired ketones chemoselectively in the presence of olefinic double bonds in 85-95% yield (cyclopentanone 70% yield)30. 

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. 

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