Chiral auxiliaries SAMP/RAMP method

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 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... 

The SAMP/RAMP Method As early as 1976, azaenolates derived from A,A-dialkyl hydrazones were studied as an alternative to direct ketone and aldehyde enolate alkylations. These species were found to exhibit higher reactivity toward electrophiles, as well as better regioselectivity for C-alkylation than their parent carbonyl compounds. A,A-diaIkyl hydrazones are stable and are relatively easy to prepare, making them appealing from a practical point of view in comparison with imines and enamines, which can be difficult to form quantitatively and are hydrolytically unstable. Given these desirable attributes, Enders undertook the development of chiral nonrace-mic A,A-diaIkyl hydrazine auxiliaries for the asymmetric a-alkylation of ketones. The result of his efforts were (5)-and (R)-l-amino-2-methoxypyrrohdine hydrazine (1 and 2, respectively), now commonly known as the SAMP and RAMP auxiliaries, respectively (Figure 7.1). Over the years, the SAMP/RAMP method has come to be considered the state-of-the-art approach to asymmetric ketone... 

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. 

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. 

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. 

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. 

Alkylation of lithiated hydrazones forms the basis of an efficient method for the asymmetric alkylation of aldehydes and ketones, using the optically active hydrazines (5)-l-amino-2-(methoxymethyl)pyrroUdine (SAMP) 59 and its enantiomer (RAMP) as chiral auxiliaries. Deprotonation of the optically active hydra-zones, alkylation and removal of the chiral auxiliary under mild conditions (ozonol-ysis or acid hydrolysis of the A-methyl salt) gives the alkylated aldehyde or ketone with, generally, greater than 95% optical purity. This procedure has been exploited in the asymmetric synthesis of several natural products. Thus, (S)-4-methyl-3-heptanone, the principal alarm pheromone of the leaf-cutting ant Am texana, was prepared from 3-pentanone in very high optical purity as shown in Scheme 1.74. 

In the late 1970s, Enders pioneered an elegant method for ketone and aldehyde alkylation involving the use of metalated chiral hydrazones [92, 93). Extensive studies with the (S)-l-amino-2-methoxymethylpyrrolidine (SAMP, 150, Scheme 3.24) auxiliary and its enantiomer RAMP established these as superb chiral auxiliaries with numerous applications. In a typical alkylation sequence, a RAMP/SAMP hydrazine is condensed with an aldehyde or a ketone to form the corresponding hydrazone, such as 152. This can subsequently be deprotonated and the resulting enolate trapped with a variety of electrophilic reagents including alkyl halides, aldehydes, Michael acceptors, silyl triflates, and disulfides. The RAMP/SAMP hydrazine auxiliary may be removed by acidic hydrolysis or ozonolysis to reveal the alkylated... 

---