SAMP-/RAMP-hydrazones

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.

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. 

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 ... 

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. 

Since only a few asymmetric syntheses are known [55], we developed an efficient asymmetric synthesis of (S,S,R)-(-F)-2-epi-deoxoprosopinine ](S,S,R)-87] employing the SAMP/RAMP hydrazone method as key steps [56]. Scheme 1.2.19 describes our retrosynthetic analysis, showing that the title alkaloid can be syn-... 

Retrosynthetic considerations among our group have revealed the possibility of using our SAMP/RAMP hydrazone methodology in combination with the synthetic building block 2,2-dimethyl-l,3-dioxan-5-one. Thus starting from the... 

As already demonstrated in the previous natural product synthesis, the alkylation of 2,2-dimethyl-l,3-dioxan-5-one SAMP/RAMP hydrazones is a reliable tool with which to synthesize chiral 4-substituted 2,2-dimethyl-l,3-dioxan-5-ones in gram quantities and with high enantiomeric excesses [68]. Thus, after metalla-tion of the RAMP hydrazone (R) -96 the corresponding lithio azaenolate was alkyl-... 

Based on our SAMP/RAMP hydrazone methodology and using our dioxanone RAMP hydrazone 96 as a chiral 1,3-dihydroxyacetone equivalent, we have been... 

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