RAMP hydrazones

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... 

R)-Enantiomer predominates. When the reaction sequence is performed with the corresponding RAMP-hydrazone, (S)-l-(4-benzyloxy-3-melhoxyphenyl)-5-hydroxy-3-decanoneis obtained in 75% yield and 39% ee17. 

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. 

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. 

Figure 2-3. Synthetic scope of the SAMP/RAMP-hydrazone method.

Ahlbrecht and coworkers showed that the stereoselective alkylation of Af-cinnamyl (5 )-2-methoxymethylpyrrolidine (STdR), followed by hydrolysis, affords enantiomerically enriched 3-substituted phenylpropionaldehydes, as shown in Scheme 45. This method is analogous to the asymmetric alkylation of S AMP/RAMP hydrazones, as the anions are isoelectronic. The mechanisms of asymmetric induction for the two systems are probably similar. For the lithio cinnamyl amine, methylation can be optimized up to 97.5% ds. Most of the procedures in this paper include potassium tert-butoxide, so the cation in these examples may be potassium. Under these conditions, methyl, primary and secondary alkyl iodides typically afford the products with selectivities in the 90-93% ds range. 

The configuration of the Claisen rearrangement product (J )-( )-2,4-dimethyl-4-heptenoic acid (see p 422)144 was determined by correlation with a reference sample of (f )-4,6-dimethyl-6-nonen-3-one (1) prepared from 3-pentanone employing the RAMP-hydrazone method221. Configurational assignment thus rests on the well-established stereochemical course of the Enders method 222. 

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... 

H-NMR spectroscopic features of SAMP/RAMP-hydrazones include a singlet for the methoxy group at 3.2 3.3 ppm and, in the case of aldehyde hydrazones, a triplet for the imine hydrogen at 6.4 6.5 ppm. 

Table I. SAMP/RAMP-Hydrazones by Deri validation of Carbonyl Compounds with SAMP/RAMP...

Cyclic ketones are alkylated via their corresponding SAMP/RAMP-hydrazones in good overall yield and excellent enantioselectivities (72-99%, see Table 2). The enantiomeric excesses can be optimized by the use of diethyl ether instead of tetrahydrofuran as solvent8-29. 

Using diethyl ether as solvent, SAMP/RAMP-hydrazones of acyclic ketones are alkylated in good chemical yield and generally enantiomeric purities of > 90 % are achieved (see Table 3). Most prominent is the preparation of the alarm pheromone of the ant, ( + )-(5T)-4-methyl-3-hep-tanone, which proceeds with practically complete asymmetric induction5,38. Lower enantiomeric excesses (10-30%) are obtained in the alkylation of ketones which contain a phenyl substituent at the alkylated carbon3,8. 

Table 2. a-Alkylated Cyclic Ketones by Alkylation of Cyclic SAMP/RAMP-Hydrazones, Followed by Cleavage"... 

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. 

For the regeneration of sensitive, optically active aldehydes and ketones from their SAMP- or RAMP-hydrazones, two mild cleavage methods are used routinely. 

SAMP/RAMP-Hydrazones are cleaved oxidatively by ozonolysis in dichloromethane at — 78 °C3. This method proceeds within 15 to 30 minutes/10 mmol in quantitative yield without racemization. The endpoint of the cleavage reaction is indicated by the green color of the yellow nitrosamine with blue ozone. Besides the desired carbonyl compound, one quivalent of (S)- or (/J)-2-methoxymethyl-l-nitrosopyrrolidine is formed. 

Table 4. a-Alkylated Aldehydes by Alkylation of SAMP/RAMP-Hydrazones, Followed by Cleavage ... 

The cleavage of a,a -disubstituted SAMP- or RAMP-hydrazones to spiroacetals is performed without racemization under acidic conditions (4-methylbenzenesulfonic acid in chloroform) by careful monitoring of the reaction by thin layer chromatography and immediate workup of the reaction after completion in order to avoid racemization. Racemic mixtures are obtained when the reaction mixture is stirred for a longer time20. 

Bestmann et al.166) used the SAMP/RAMP-hydrazone method very successfully in their synthesis of both enantiomers of methylsubstituted pheromone analogues (150) of Lepidopetra species Manestra brassicae (R = n-C4H9), Argyrotaenia velu-tinana, Ostrinia nubilalis and Tortrix viridana (R = C2HS). 

ElectrophiHc substitutions with carbon and hetero electrophiles a to the carbonyl group of aldehydes and ketones are among the most important synthetic operations. Such regio-, diastereo-, and enantioselective substitutions can be carried out efficiently with the SAMP/RAMP hydrazone methodology [3]. For cases where virtually complete asymmetric inductions could not be attained, an alternative approach based on a-silylated ketones 2 was developed [4]. They can be prepared easily from ketones 1 in high enantiomeric purity (ee > 98%) by asymmetric carbon silylation employing the SAMP/RAMP hydrazone method (Fig. 1.1.1). After the introduction of various electrophiles via classical enolate chemistry with excellent asymmetric inductions, the desired product ketones 3... 

I J.2 Natural Products Employing the SAMP/RAMP Hydrazone Methodology... 

For the synthesis of the second required building block, the chiral allylic bromide 31, we again used our SAMP/RAMP hydrazone methodology for the construction of the stereogenic center. The a-alkylation of the SAMP hydrazones of O-protected 4-hydroxybutanal 40a,b with iodomethane led to the desired products 41 with very good yields and very high stereoselectivities and with the required... 

Neonepetalactone, 61 (Fig. 1.2.3), a bioactive compound found to be quite attractive to cats [41], was isolated in 1965 from the leaves and galls of Actinidia polygama by T. Sakan et al. and its absolute configuration was determined in 1980 [41b]. As some syntheses of the racemic mixture or ex-chiral-pool syntheses had already been reported, we realized that our SAMP/RAMP hydrazone methodology would make it possible to develop a very short asymmetric synthesis of this bioactive 8-lactone. 

Starting from the RAMP hydrazone (R)-67, which can easily be prepared from n-pentanal and RAMP in a multigram quantity, the electrophilic substitution (after metallation with LDA) using 2-(2-iodoethyl)-l,3-dioxolane (68) provided... 

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