Ramp and Samp

A number of commonly used auxiliaries are available in both enantiomeric forms, for example the proline-derived auxiliaries RAMP and SAMP [18] giving rise to the complementary stereoselecting reactions. However, many natural carbohydrates are available in only one configuration. The other enantiomer (usually the L-form) is very expensive in most cases and difficult to prepare. 

An alternative to hydrolysis is cleavage of the RAMP- and SAMP-hydrazones by ozonolysis which takes place without epimerization or racemizationA This is a reliable method of obtaining the alkylated ketone products with high de and ee selectivity. ... 

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. 

Enders and coworkers reported studies in which the RAMP and SAMP chiral auxiliaries were employed in the aza-annulation process (Scheme 39).1,4 Condensation of 179 with RAMP provided a route to the optically active enamino hydrazone 473, which was then metalated with nBuLi to generate the corresponding anion. Aza-annulation of 473 with 474 produced intermediate 475, which could be cyclized slowly (2 d) at 60 °C to give 476. Alternatively, heterocycle formation could be facilitated by an increase in reaction temperature (toluene, heat). Removal of the chiral auxiliary gave 477 in 50-52% overall yield from 179 in >99 1 enantiomeric purity. Substituents on the aromatic ring did not have a measureable effect on the yield of the aza-annulation reaction. 

The same prohne-derived ring system features in Enders RAMP and SAMP chiral hydrazone auxiharies, and Enders [42-45] has shown than RAMP and... 

A brief investigation using chiral auxiliaries such as Ender s RAMP and SAMP, provided a route to a-disubstituted ketones (32) with a moderate degree of chiral induction [152] (Scheme 69). 

Enders synthesises this simple compound, the defence secretion of the daddy longlegs insect, Leiobunum vittatum and L. calcar, to illustrate the use of his RAMP and SAMP chiral auxiliaries (see section 5.3.2). The imine of 3-pentanone and SAMP is deprotonated with LDA, and the anion alkylated with -l-bromo-2-methylbut-2-... 

Chronologically, the successful and efficient asymmetric alkylation of enolates was preceded by the development of chiral azaenolates indeed, the meanwhile classic reagents hke Meyers oxazolines [4], Enders hydrazones RAMP and SAMP [5], and Schollkopf s bislactim ethers [6] were the first auxiharies to enable carbon-carbon bond formation with high (overall) enantioselectivity. 

The easiest way to make oxidizable silanes is by condensation of an organolithium with the inexpensive dimethyldimethoxysilane. If enolates have to be silylated, it may be preferable to use the more reactive chlorodimethylalkoxysilanes. Introduced by Dieter Enders, a-lithiated RAMP- and SAMP-hydrazones (e.g., 78) are enolate-like species having an impressive track record for stereocontrolled synthesis. The chiral auxiliary enables the stereoselective introduction of the silicon substituent. Having oxidatively cleaved the hydrazone to restore the original carbonyl function, the latter may be diastereoselective reduced to either an (/ )- or (5)-alcohoI. The ultimate silicon/oxygen displacement thus produces either a meso- or a dl-Aio (Scheme 1-55). ... 

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]). 

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. 

Applications include typical carbanionic reactions of the RAMP- or SAMP-hydrazones of carbonyl compounds, such as alkylations and silylations (Section D.9.), Michael additions (Sections D.l.5.2.3. and D.I.5.2.4.), hydroxylations ofazaenolates (Section D.4.I.), etc. Yields and enantioselectivities of the products are generally high. 

Commercial (S)- and (R)-1 -amino-2-methoxypyrrolidines (SAMP and RAMP) can be synthesized from either prolines or glutamic acids. They are widely used for the stereoselective a-alkylation of aldehydes. One first forms the hydrazone with SAMP or RAMP and then alkylates in the presence of lithiu-mamide at low temperature. The optical purity is usually in the order of 90%, but enantiomeric excesses of 95% may also be obtained with large alkylbromides (Scheme 9.4.14) (Coppola and Schuster, 1987). 

Remarkable diastereoselectives have also been observed for AHR with the chiral auxiliaries RAMP or SAMP (Scheme and with the chiral snlfoxides (Scheme... 

Asymmetric electrophilic substitution of aldehydes and ketortes via (S) or (R)-1-amino-2-methoxymethylpyrrolldine (SAMP or RAMP) hydrazones. 

S)- and (+ )-(7 )-l-Amino-2-(methoxymethyl)pyrrolidine- (SAMP and RAMP)-hydrazones derived from methyl ketones and chiral hydrazines are metalated regioselectively at the methyl... 

Metalated SAMP- or RAMP-hydrazones derived from alkyl- or arylethyl ketones 3 add to arylaldehydes both diastereo- and enantioselectively. Substituted / -hydroxy ketones with relative syn configuration of the major diastereomer are obtained with de 51-80% and 70-80% ee. However, recrystallization of the aldol adducts, followed by ozonolysis, furnishes diastereo- and enantiomerically pure (lS, S )-. yn-a-mcthyl-/3-hydroxy ketones 5 in 36-51% overall yield. The absolute configuration of the aldol adducts was established by X-ray crystallographic analysis. Starting from the SAMP- or RAMP-hydrazone either enantiomer, (S,S) or (R,R), is available using this methodology16. 

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. 

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. 

The Enders method has also been used as a key step in the synthesis of optically active Ar-heterocycles. The use of cyclic 1,3-diketones for the preparation of the SAMP or RAMP lithium azaenolates is shown by the synthesis of substituted 4,6,7,8-tetrahydro-2,5(l//,3//)-quinolinediones 2. Michael addition of 1 with, for example, benzylidene propanedioates followed by removal of the auxiliary and lactamization gives 2 with > 98% ee201. 

Additions of stabilized carbanions to imines and hydrazones, respectively, have been used to initiate domino 1,2-addition/cyclization reactions. Thus, as described by Benetti and coworkers, 2-subshtuted 3-nitropyrrolidines are accessible via a nitro-Mannich (aza-Henry)/SN-type process [165]. Enders research group established a 1,2-addition/lactamization sequence using their well-known SAMP/ RAMP-hydrazones 2-308 and lithiated o-toluamides 2-307 as substrates to afford the lactams 2-309 in excellent diastereoselectivity (Scheme 2.72) [166]. These compounds can be further transformed into valuable, almost enantiopure, dihydro-2H-isoquinolin-l-ones, as well as dihydro- and tetrahydroisoquinolines. 

Enders developed the hydrazone methods by choosing SAMP and its enantiomer RAMP. The application and scope of SAMP/RAMP are summarized in Figure 2-3. SAMP and RAMP can be prepared on a large scale from (S)-proline36 and (R)-glutamic acid,37 respectively. 

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... 

Excellent enantioselectivities up to complete asymmetric induction are achieved in the preparation of a-alkylated aldehydes, acyclic and cyclic ketones via (-)-(S)- and (+ )-(7 )-1 -amino-2-methoxymethylpyrrolidine (SAMP/RAMP-hydrazones) (see Section 1.1.1.4.2.). Due to the unique mechanism of metalation and alkylation, the absolute configuration of the final products can be predicted. Since both antipodes of the auxiliary are available, either enantiomer of the desired alkylated carbonyl compound can be prepared... 

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 ... 

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