SAMP hydrazine

This protocol allows to break the C=N double bond to afford the corresponding carbonyl compound along with A-nitrosamine 3, a precursor of the SAMP hydrazine which can thus be recycled (Scheme 2.29). 

Concerning the hydrolytic cleavage conditions, one method was reported by Enders in his seminal study in 1976 [8]. The latter consists in the alkylation of the nitrogen with an excess of iodomethane to form the corresponding ammonium salt, which is hydrolyzed in a biphasic HCl 1 M/n-pentane system. In 1998, Enders described very mild conditions using a saturated aqueous solution of oxalic acid in ether, which allowed to hydrolyze the hydrazones without racemization [12]. This protocol has also the advantage of recycling the chiral SAMP hydrazine. 

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... 

Enders demonstrated that N-silylated SAMP hydrazine 105 can be used as a nucleophile in conjugate addition additions. For example, the lithiated tri-methylsilyl hydrazine derived from 105 was shown to undergo addition to... 

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... 

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. 

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. 

Chiral amines.1 These reagents also add to imines and this reaction can be used for synthesis of optically active amines. Thus RCeCl2 adds to SAMP-hydra-zones (12, 30) to form hydrazines in good yield and high diastereoselectivity. These are reduced to optically active amines by hydrogenation catalyzed by Raney nickel. The hydrazines are prone to oxidation, but can be isolated as the stable carbamates. 

The preparation of a chiral bicyclic hydrazine, (15,35,5S)-2-amino-3-methoxymethyl-2-azabi-cyclo[3.3.0]octane (SAMBO, 3), was reported32 in 1990. (12 S, 31 S,51 5 )-2-Azabicyclo[3.3.0]-octane-3-carboxylic acid was resolved into its enantiomers. The (lS ,35,55)-enantiomer was converted to the chiral hydrazine 3 in six steps, utilizing Hofmann degradation, which is also employed in the preparation of SAMP. 

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. 

Reduction of alkylated aldehyde-derived SAMP-hydrazones, followed by reductive N —N cleavage of the resulting hydrazines with Raney nickel, furnishes /(-substituted primary amines in good chemical yields and without racemization in 94-99% ee (see Table 5)31. 

During our investigations on asymmetric C—C bond formation reactions via conjugate addition of SAMP hydrazones to various a,(3-unsaturated Michael acceptors, it occurred to us to use the chiral hydrazine auxiliary S AM P as a nitrogen nucleophile and a chiral equivalent of ammonia in aza-Michael additions. Thus, we developed diastereo- and enantioselective 1,4-additions for the synthesis of P-amino acids and P-aminosulfonates [14, 15]. 

The enantiomerlcally pure hydrazines SAMP and RAMP are versatile chiral... 

ASYMETRIC SYNTHESES USING THE SAMP-/RAMP-HYDRAZINE ttTHOD (S)-(+)-4-METHYL-3-HEPTAN0NE (3-Heptanone, 4-methyl, (S)-)... 

An efficient asymmetric synthesis of the 3-substituted /3-sultams 163 has been reported. The key step of the synthesis is the Lewis acid-catalyzed aza-Michael addition of the enantiopure hydrazines (A)-l-amino-2-methoxy-methylpyrrolidine (SAMP) or CR,l ,l )-2-amino-3-methoxymethyl-2-azabicyclo[3.3.0]octane (RAMBO) to the alke-nylsulfonyl sulfonates 176. /3-Hydrazino sulfonates were obtained in good yield and excellent enantioselectivity. Cleavage of the sulfonates followed by chlorination resulted in the corresponding sulfonyl chlorides 177. The (A)-3-substituted /3-sultams 163 have been obtained in moderate to good yields and high enantioselectivity over two steps, an acidic N-deprotection followed by in situ cyclization promoted by triethylamine (Scheme 55) <2002TL5109, 2003S1856>. 

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. 

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... 

An efficient approach for asymmetric syntheses of benzo[ ]furan-l-alkylamines was developed by reaction of 2-lithiated benzoMfuran with aldehyde-SAMP-derived hydrazones (SAMP = (3 )-(—)-l-amino-2-methoxymethyl-pyrolidine Equation 84). In this way, an efficient synthesis of hydrazine 91 was achieved <2004TA747>. 

Further applications can be mentioned briefly. SAMP was used in the resolution of 4-demethoxy-7-deoxydaunomycinone/ in ee determinations (Scheme 1), as a chelate for tetracarbonylmolybdenum complexes/ in intramolecular Heck reactions, as polysilylated hydrazine, in the enantioselective synthesis of isoquinuclidines, and in the conversion of hydrazones to aldehydes and nitriles. The structure of a chiral lithium SAMP hydrazone azaenolate has been determined. In cases where SAMP did not lead to satisfactory inductions, a modified auxiliary, (S)-l-amino-2-dimethylmethoxymethylpyrrolidine (SADP), enhanced the stereochemical control. 

Reaction of 3-pentanone with the commercially available hydrazine (5)-l-amino-2-methoxymethylpyrrolidine (SAMP) affords the corresponding chiral hydrazone. Deprotonation with LDA followed by alkylation and hydrolysis furnishes (S)-4-methyl-3-heptanone in greater than 99% enantiomeric excess. Using the corresponding (R)-hydrazine (RAMP) provides (R)-4-methyl-3-heptanone. 

Enders, D. TMS-SAMP. Novel chiral hydrazine auxiliary for hetero-Michael additions and aza-Peterson olefinations. Acros Organics Acta 1995, 1, 37-38. 

Cleavage of hydrazines. Hydrogenolysis follows addition of alkyllithiums to SAMP/RAMP hydrazones in chiral amine synthesis (13 examples, 41-73%). 

The use of hydrazines as chiral auxiliaries was initiated by Enders and coworkers [315]. They have developed the chemistry of hydrazones derived from epimeric 1 -amino-2-methoxymethylpyrrolidines 1.76, Samp and Ramp [161, 169, 253, 261, 315, 316], These compounds are commercially available, or they can easily be prepared from (S)-prolinol 1.64 (R = CH2OH) or (R)-glutamic add [261]. Hydrazones have some advantages over their related imine derivatives. First, they are formed in quantitative yield even from sterically hindered ketones. Second, their derived anions are often more reactive than the related aldehyde or ketone enolates. 

For the asymmetric alkylation of ketones and aldehydes, a highly practical method was developed by the Enders group, and uses SAMP-RAMP hydrazones (reviews [104-107]). SAMP and RAMP are acronyms for orR-l-amino-2-methoxymethylpyrrolidine. This chiral hydrazine is used in an asymmetric version of the dimethylhydrazone methodology originally developed by Corey and Enders... 

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