SAMP/RAMP chiral auxiliaries

Prolinol methyl ether 31 is used in Enders s SAMP and RAMP chiral auxiliaries (chapter 27) and (S)-()-SAMP 32 can be made in 50-58% overall yield from (S)-L-(—) -proline on a 75 g scale.12... 

In independent studies, Denmark noted that the yields in additions of or-ganometallic species to enolizable SAMP-derived hydrazones such as 78 were generally improved by employing the less basic organocerium reagents (Equation 7) [71]. These findings further expand the scope for the use of SAMP and RAMP chiral auxiliaries in asymmetric C=N additions. 

An excellent synthetic method for asymmetric C—C-bond formation which gives consistently high enantioselectivity has been developed using azaenolates based on chiral hydrazones. (S)-or (/ )-2-(methoxymethyl)-1 -pyrrolidinamine (SAMP or RAMP) are chiral hydrazines, easily prepared from proline, which on reaction with various aldehydes and ketones yield optically active hydrazones. After the asymmetric 1,4-addition to a Michael acceptor, the chiral auxiliary is removed by ozonolysis to restore the ketone or aldehyde functionality. The enolates are normally prepared by deprotonation with lithium diisopropylamide. 

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... 

The interesting structures of the Lasioderma compounds have been the subject of many syntheses, serving as models for stereocontrolled approaches. More recent syntheses of serricornin form two groups those using chiral auxiliaries (oxazolidinone [250],boronic esters [251],and SAMP/RAMP [252]) and those involving chemoenzymatic steps ([253-255]). 

In contrast to the variety of chiral auxiliaries which have been used in the asymmetric alkylation of imine-derived azaenolates (see Section 1.1.1.4.1Table 7), alkylations of the hydrazone analogues employ mainly (-)-(S)-l-amino-2-methoxymethylpyrrolidine (SAMP) and its opti-cal antipode (RAMP). r A oCH, O ... 

Alkylated Carbonyl Compounds and Recovery of the Chiral Auxiliary by Cleavage of Alkylated SAMP/ RAMP-Hydraznnes General Procedure for Ozonolysis3 ... 

The (R)- and (S)-enantiomers of (E)-4.6-dimethyl-6-octene-3-one (147), a defense substance of spiders (known commonly as daddy longlegs Leiobunum vittatum and L. calcar) were recently synthesized by Enders and Baus 163> using the (R)-proline derivative RAMP and the (S)-proline derivative SAMP (137) as chiral auxiliary, respectively. (S)- and (R)-enantiomers of (147) have been obtained in an overall chemical yield of 70% and in very high stereoselectivities of 95% e.e., respectively. 

In continuation of our efforts to explore the utility of the SAMP/RAMP hydra-zone methodology, we developed the first asymmetric synthesis of a-phosphino ketones via formation of a carbon-phosphorus bond in the a-position to the carbonyl group [70]. The key step of this asymmetric C—P bond formation is the electrophilic phosphinylation of the ketone SAMP hydrazone 87, giving rise to the borane-adduct of the phosphino hydrazone 88 with excellent diastereoselectiv-ity (de = 95-98%). Since these phosphane-borane adducts are stable with respect to oxidation, the chemoselective cleavage of the chiral auxiliary by ozonolysis leading to the a-phosphino ketones (R)-89 could be accomplished with virtually no racemization. Using RAMP as a chiral auxiliary, the synthesis of the enantiomer (S)-89 was possible (Scheme 1.1.25). 

Dieter Enders, Peter Fey, and Helmut Kipphardt 173 (S)-(-)-1-AMIN0-2-METH0XYMETHYL-PYRROLIDINE (SAMP) AND (R)-(+)-l-AMIN0-2-METH0XYMETHYLPYRR0LIDINE (RAMP). VERSATILE CHIRAL AUXILIARIES... 

The three-step procedure described here, using inexpensive, commercially available starting materials and the chiral auxiliary SAMP, Illustrates the synthetic utility of the "SAMP-/RAMP-hydrazone method".18 It is remarkable that the classical electrophilic substitution of a conformationally flexible, acyclic ketone 1 (S)-4 occurs with virtually complete asymmetric... 

Many chiral auxiliaries are derived from 1,2-amino alcohols.7 These include oxazolidinones (l),7-9 oxazolines (2),10 11 bis-oxazolines (3),1213 oxazinones (4),14 and oxazaborolidines (5).15-17 Even the 1,2-amino alcohol itself can be used as a chiral auxiliary.18-22 Other chiral auxiliaries examples include camphorsultams (6),23 piperazinediones (7),24 SAMP [(S)-l-amino-2-methoxy-methylpyrrolidine] (8) and RAMP (ent-8),25 chiral boranes such as isopinocampheylborane (9),26 and tartaric acid esters (10). For examples of terpenes as chiral auxiliaries, see Chapter 5. Some of these auxiliaries have been used as ligands in reagents (e.g., Chapters 17 and 24), such as 3 and 5, whereas others have only been used at laboratory scale (e.g., 6 and 7). It should be noted that some auxiliaries may be used to synthesize starting materials, such as an unnatural amino acid, for a drug synthesis, and these may not have been reported in the primary literature. 

Enders and coworicers have shown that deprotonation of chiral SAMP/RAMP hydrazones (or their substituted analogs) derived from ketones or aldehydes, followed by reaction with Davis oxaziridine reagent provides the a-hydroxy hydrazones in moderate yield but with high diastereoselectivity. Direct unmasking or protection followed by unmasking provides the corresponding a-hydroxy ketones or aldehydes respectively (Scheme 24). Both antipodes of the hydroxylated compounds are available by appropriate choice of (5)- or (R)-proline-deiived auxiliaries. The direction of induction is predictable, if not wholly uniform (R substitution alters the a-stereochemistry for aldehyde hydrazones). The process clearly provides a valuable approach to both systems. 

A, A -Dialkylhydrazones are often converted into the carbonyl form by a variety of oxidative methods. The respective compounds (like 100) shown in Scheme 93, derived from proline-based systems (RAMP and SAMP), are widely used as potent chiral auxiliaries and have provided a very versatile method for the diastereoselective a-alkylation of ketones. SAMP and RAMP hydrazones can be cleaved with O3, by reductive techniques and by hydrolysis with strong acids. 

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