Hydrazone SAMP/RAMP-derived

The use of hydrazone or enamine derivatives of ketones or aldehydes offers the advantage of stcreocontrol via chelated azaenolates. Extremely useful synthetic methodology, with consistently high anti selectivity, has been developed using azaenolates based on (S)- or (R)-l-amino-2-(methoxymethyl)pyrrolidine (SAMP or RAMP)51 58 (Enders method, see Section 1.5.2.4.2.2.3.). An example which illustrates the efficiency of this type of Michael addition is the addition of the lithium azaenolate of (5 )-l-amino-2-(methoxymethyl)pyrrolidine (SAMP) hydrazone of propanal (R = II) to methyl (E )-2-butenoate to give the nub-isomer (an 1 adduct) in 80% yield with a diastereomeric ratio > 98 2,... 

Aldehyde-derived SAMP/RAMP-hydrazones are alkylated in good overall chemical yields and excellent enantiomeric purities (see Table 4). Asymmetric inductions of up to 86% ee, obtained from alkylation reactions in tetrahydrofuran, were optimized to >90% ee by using diethyl ether as solvent8. Phenyl-substituted aldehydes are alkylated to products of lower enantiomeric purity (23-31 % ee), probably due to partial racemization of the sensitive aldehydes6, 25. 

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. 

The basic concept, although most likely not the detailed mechanism, of the Enders asymmetric induction follows from the chelation-controlled asymmetric alkylation of imine anions introduced by Meyers and Whitesell. The hydrazones derived from either the (5)- or the (/ )-enantiomer of iV-amino-2-methoxymethylpyrrolidine (SAMP and RAMP, derived from the amino acid proline) can be converted to anions that undergo reaction with a variety of electrophiles. After hydrolysis of the product hydrazones, the alkylated ketones can be obtained with good to excellent levels of optical purity (Scheme 19). 

The deprotonation of the SAMP/RAMP hydrazone derivatives leads to the formation of azaenolates that can be trapped by the alkyl halide. In theory, four isomeric azaenolates can form in the deprotonation step, but it was shown that around the C-C double bond stereochemistry is dominant, while around the C-N bond Z stereochemistry EccZcn is dominant for cyclic- and acyclic ketones. This observation was confirmed by trapping experiments,... 

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. 

Aza-enolates derived from imines were introduced in chapter 10. It is easy to see that imines from chiral amines might well be used to make aza-enolates that would react asymmetrically with electrophiles. Among the most famous examples are the hydrazones SAMP and RAMP derived by Enders from proline.3 The starting material derived from natural (S )-(-)-proline 17 is called SAMP 18 and the one derived from unnatural (R)-(+)-proline is RAMP. The reactions of the two are identical except that they lead to products of opposite chirality. 

Good results are obtained from reactions of compounds containing chiral auxiliaries. Thus, 1,3-asymmetric induction in the addition of radicals to 30, 1,4-asymmetric induction by the isopropyl group of the dilactim derived from cyclo(Gly-Val) in the addition to conjugated sulfones, and 1,5-asymmetric induction for SAMP/RAMP hydrazones during the addition to alkenylphosphonate esters are adequate. 

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... 

A variety of other methods have been employed on a case-by-case basis to effect auxiliary cleavage, and a detailed account of these methods is available. In addition to hydrolytic approaches, for aldehyde hydrazones, a number of convenient direct methods are available that allow the auxiliary to be cleaved in such a way that a functional group other than an aldehyde is generated. For instance, aldehyde-derived SAMP/RAMP hydrazones can be directly converted into the corresponding nitriles, ° amines,or dithianes, thereby enabling subsequent reactivity not immediately available from the aldehyde itself (Scheme 7.5). 

In comparison with ketone-based SAMP/RAMP hydrazones, the use of aldehyde-derived SAMP/RAMP hydrazones in natural product syntheses is much more prevalent. For instance, Nicolaou et al. synthesized the side chain of zaragozic acid A 49 using two successive SAMP hydrazone alkylations (Scheme 1.1) The zaragozic acid class of natural products inhibits squalene synthase, the enzyme responsible for the biosynthesis of cholesterol. Inhibition of this enzyme has implications in the treatment of coronary artery disease. The synthesis of the side chain of zaragozic acid began with the formation of 42, which... 

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. 

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 ... 

A highly selective method for the preparation of optically active 3-substituted or 3, y-disubstituted-S-keto esters and related compounds is based on asymmetric Michael additions of chiral hydrazones (156), derived from (5)-l-amino-2-methoxymethylpyrrolidine (SAMP) or its enantiomer (RAMP), to unsaturated esters (154).167-172 Overall, a carbonyl compound (153) is converted to the Michael adduct (155) as outlined in Scheme 55. The actual asymmetric 1,4-addition of the lithiated hydrazone affords the adduct (157) with virtually complete diastereoselection in a variety of cases (Table 3). Some of the products were used for the synthesis of pheromones,169 others were converted to 8-lactones.170 The Michael acceptor (158) also reacts selectively with SAMP hydrazones.171 Tetrahydroquinolindiones of type (159) are prepared from cyclic 1,3-diketones via SAMP derivatives like (160), as indicated in Scheme 56.172... 

Since Kagan s first report of N-N bond reduction using Sml2,39 the reagent is now routinely used for the transformation. The reaction has been used widely in asymmetric synthesis to reduce the products of asymmetric additions to, or reductions of,47 hydrazone derivatives. For example, Enders reported the nucleophilic addition of alkyllithiums to trifluoroacetaldehyde SAMP and RAMP hydrazones in an asymmetric approach to a-trifluoromethyl-sub-stituted amines.48 After activation of the adducts by benzoylation, Sml2-mediated N-N bond cleavage proceeded in high yield (Scheme 4.41). 

Michael addition of trialkylstannyllithium to cyclohexenone SAMP- or RAMP-hydrazone gives 3-stannyl derivatives with de values of 42-44%, while subsequent alkylation of the enolate formed affords trans-products with de values >96%. The hydrazones obtained are subjected to ozonolysis to give 3-stannylcyclohexanones trans-1 with ee values up to 96%17. 

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. 

Fortunately, the use of lithiated hydrazones derived from (S)- or ( )-l-amino-2-methoxymethylpyiro-lidine (SAMP or RAMP) as nucleophiles for asymmetric alkylations have provided a solution to the problems described above with metallated acyclic ketimines and aldimines. Lithiated SAMP or RAMP hydrazones of cyclic ketones are also alkylated in high yields. A major advantage of these chiral hydrazones is that their derivatives of aldehydes, acyclic and cyclic ketones all yield mainly ( )cc-. (Z)cN-Iithiated species on deprotonation with LDA in ethereal solvents under kinetic control. The ( )cc-configuration obtains as a result of the minimization of steric interactions in the usual closed transition... 

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. 

Instead, we turned our attention to the asymmetric alkylation of y-butyrolactone or its (o-hydroxy esters derivatives. The work by Enders and co-workers using SAMP or RAMP lactone hydrazones has shown great success with six- and seven-membered ring lactones. We decided to examine the use of this protocol in a five-membered ring analogue. 

Diastereoselectivity is also observed in reactions of carbanions derived from imines and hydrazones, when those species contain a chiral center or a chiral auxiliary (sec. 9.4.F). Asymmetric imines can be used, and chiral oxazoline derivatives have also been prepared and used in the alkylation sequence (sec. 9.3.A). Meyers showed that chiral oxazoline 478 could be alkylated to give the ethyl derivative, 479. A second alkylation generated the diastereomeric product 480, and hydrolysis provided the chiral lactone (481) in 58% yield and with a selectivity of 70% ee for the (R) enantiomer. 53 As pointed out in Section 9.4.F.ii, hydrazone carbanions can be used for alkylation or condensation reactions. In a synthesis of laurencin. Holmes -l prepared the asymmetric hydrazone 483 (prepared by Enders by reaction of cycloheptanone and the chiral hydrazine derivative called SAMP, 482-A-amino-(2S)-(methoxymethyl)pyrrolidine)- - and showed that treatment with LDA and reaction with iodomethane gave an 87% yield of the 2-ethyl derivative in >96% de. Ozonolysis cleaved the SAMP group to give (/ )-2-ethylcycloheptane (484) in 69% yield. The enantiomer of 482 is also known (it is called RAMP, A-amino-(27 )-(methoxymethyl)pyrrolidine). 

Chiral hydrazones derived from SAMP or RAMP are used in the asymmetric synthesis of 4,5,6-trisubstituted and 6-substituted piperidinones <97LA1115>. Chiral 2-substituted piperidines are prepared by the addition of Grignard reagents to chiral imines followed by oxidation of the terminal double bond and reductive cyclization <97JOC746>. 

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

Preparation of a-Silyl Ketones. SAMP- and RAMP-hydra-zones of methyl ketones have been converted into a-silyl ketones using thexyldimethylsilyl chloride.For example, the SAMP-hydrazone of 2-butanone 18 was deprotonated with LiTMP, and the intermediate anion was treated with thexyldimethylsilyl chloride to form the a-silyl derivative 19 in high yield (eq 9). When other dialkyl ketones were used, thexyldimethylsilyl triflate was required for silylation to occur, but poor regioselectivity was observed. ... 

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