Enders’ SAMP

The aldimine of Figure 13.34 is a chiral and enantiomerically pure aldehydrazone C. This hydrazone is obtained by condensation of the aldehyde to be alkylated, and an enantiomerically pure hydrazine A, the S-proline derivative iS-aminoprolinol methyl ether (SAMP). The hydrazone C derived from aldehyde A is called the SAMP hydrazone, and the entire reaction sequence of Figure 13.34 is the Enders SAMP alkylation. The reaction of the aldehydrazone C with LDA results in the chemoselective formation of an azaenolate D, as in the case of the analogous aldimine A of Figure 13.33. The C=C double bond of the azaenolate D is fraws-configured. This selectivity is reminiscent of the -preference in the deprotonation of sterically unhindered aliphatic ketones to ketone enolates and, in fact, the origin is the same both deprotonations occur via six-membered ring transition states with chair conformations. The transition state structure with the least steric interactions is preferred in both cases. It is the one that features the C atom in the /3-position of the C,H acid in the pseudo-equatorial orientation. 

Fig. 13.34. Enders SAMP method for the generation of enantiomerically pure a-alky-Lated carbonyl compounds SAMP, (S)-aminoprolinol methyl ether = (5)-2-methoxymethyl-l-pyrrolidin-amine, or S-l-amino-2-(methoxymethyl)pyrrolidine (which is the name according to IUPAC rules).

The aldimine of Figure 10.31 is a chiral and enantiomerically pure aldehydrazone C. This hydrazone is obtained by condensation of the aldehyde, which shall be alkylated, and an enantiomerically pure hydrazine A (see Table 7.2 for the mechanism), the S-proline derivative Aaminoprolinol methyl ether (SAMP). The hydrazone C derived from aldehyde A is called the SAMP hydrazone, and the entire reaction sequence of Figure 10.31 is the Enders SAMP procedure. The reaction of the aldehydrazone... 

While the sultame and the oxazolidinone auxiliaries represent carboxylate equivalents, which have to be reduced (and sometimes re-oxidized) to the required aldehyde function at C7, the strength of Enders SAMP and RAMP auxiliaries is their direct use as aldehyde and ketone equivalents. However, Nicolaou et al. [13, 16] for the synthesis of the protected building blocks 17a-c had to give up the correct oxidation state in order to allow necessary later manipulations. Considering the necessity of reduction, the cheaper and recoverable Evans-oxazolidinones 18 appear to be the auxiliaries of choice, as demonstrated by Schinzer et al. [21, 22, 36]. A similar methylation is described in an early publication of De Brabander et al. [38] where sultame 21 was methylated and reduced to the a-methylaldehyde 20b in only two steps in good yield and enantiomeric excess. 

The synthesis of (-)-Cio-desmethyl arteannuin B, a structural analog of the antimalarial artemisinin, was developed by D. Little et a. In their approach, the absolute stereochemistry was introduced early in the synthesis utilizing the Enders SAMP/RAMP hydrazone alkylation method. The sequence begins with the conversion of 3-methylcyclohexenone to the corresponding (S)-(-)-1-amino-2-(methoxymethyl)pyrrolidine (SAMP) hydrazone. Deprotonation with lithium diisopropylamide, followed by alkylation in the presence of lithium chloride at -95 °C afforded the product as a single diastereomer. The SAMP chiral auxiliary was removed by ozonolysis. 

The total synthesis of (-)-denticulatin A, a polypropionate metabolite, was accomplished in the laboratory of F.E. Ziegler. To establish the absolute stereochemistry at C12, they utilized the Enders SAMP/RAMP hydrazone alkylation. To this end, the RAMP hydrazone of 3-pentanone was successfully alkylated with 1-bromo-2-methyl-2( )-pentene. Hydrolysis of the hydrazone under standard acidic conditions led to loss of the enantiomeric purity. This problem was avoided by using cupric acetate for the cleavage. 

The first asymmetric total synthesis of (+)-maritimol, a diterpenoid natural product that possesses a unique tetracyclic stemodane framework was accomplished by P. Deslongchamps. To introduce the C12 stereocenter, the Enders SAMP/RAMP hydrazone alkylation was used. This stereocenter played a crucial role in controlling the diastereoselectivity of the key transannular Diels-Alder reaction later in the synthesis. The required SAMP hydrazone was formed under standard conditions using catalytic p-toluenesulfonic acid. Subsequent protection of the free alcohol as a f-butyidiphenylsilyl ether, deprotonation of the hydrazone with LDA and alkylation provided the product in high yield and excellent diastereoselectivity. The hydrazone was converted to the corresponding nitrile by oxidation with magnesium monoperoxyphthalate. 

Application of the Enders SAMP/RAMP hydrazone alkylation method on 1,3-dioxan-5-one derivatives leads to versatile C3 building blocks. To demonstrate the usefulness of the above method, the research group of D. Enders applied it during the first asymmetric total synthesis of both enantiomers of streptenol A. " To obtain the natural isomer, the RAMP hydrazone of 2,2-dimethyl-1,3-dioxan-5-one was used as starting material. This compound was deprotonated with f-butyllithium and alkylated with 2-bromo-1-fert-butyldimethylsilyloxyethane. The chiral auxiliary could be hydrolyzed under mildly acidic conditions to provide the ketone in excellent yield and enantioselectivity. 

Related reactions Enders SAMP/RAMP hydrazone alkylation ... 

This isolated example which echoes the hydrazone work of Enders ( SAMP and RAMP ) no doubt illustrates a more widely applicable principle. Closely related organotin enamines afford the same product (172) with acrylates but usually in poorer chemical and optical yields.A first example of an asymmetric additive Pummerer rearrangement, (173)— (174), an uncommon reaction in its racemic form, is featured in a new route to the 6-keto-ester, (-)-methyl jasmonate (175), having ca. 20% enantiomeric purity (Scheme 13). 

As part of studies directed at leukotriene B4 receptor antagonists, Djuric et al. [66] resolved the chromanone (44) by derivatization of the ketone functionality with Enders SAMP auxiliary [67] and separation of the resulting... 

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