2-Methoxymethylpyrrolidines, chiral

The conjugate addition to acyclic enones is summarized in Table 5. The chiral hetero-cuprate derived from (S)-prolinol or cinchonidine produced products of low enantiomeric excess on treatment with chalcone (entries 3 and 4), while the cuprate from (S)-yV-methylpro-linol gave 64% ee (entry 6). Under more dilute conditions, 88% cc was obtained (entry 5). (2[Pg.909]

Barluenga et al. have described novel vinylcarbene complexes containing a cyclic BF2 chelated structure which temporarily fixes the s-cis conformation of the exocyclic C=C and Cr=C double bonds. These boroxycarbene complexes behave as dienophiles with 2-amino-l,3-butadienes in a remarkably regio- and exo-selective way. Moreover, high degrees of enantioselectivity are reached by the use of chiral 2-aminodienes derived from (S)-methoxymethylpyrrolidine [101] (Scheme 54). 

The use of chiral auxiliaries has been developed into elegant three-step sequences to achieve high ee s (Figure 2). In the general scheme a ketone is derivatized with a chiral amine. Low temperature lithiation and alkylation followed by hydrolysis produces the alkylated ketone in moderate to excellent ee s. The auxiliaries most often used are (S)-valine tert-butyl ester (Koga), l-amino-2-methoxymethylpyrrolidine (Enders) and (S)-2-amino-1-... 

Other amine-based chiral auxiliaries used instead of the 2-methoxymethylpyrrolidine gave much poorer results30. 

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... 

S)-(-)-l-AMINO-2-METHOXYMETHYLPYRROLIDINE (SAMP) AND (R)-(+)-l-AMIN0-2-ICTH0XYMETHYLPYRR0LIDINE (RAMP), VERSATILE CHIRAL AUXILIARIES (1-Pyrrolidinamlne, 2-(methoxymethyl)-, (S)) (l-Pyrrolidinamine, 2-(methoxymethyl)-, (R))... 

The use of a chiral enamine (81) derived from ( )-2-methoxymethylpyrrolidine and an achiral ester (78 R = Me) again resulted in complete anti-diastereoselectivity and an enantiomeric excess in favour of 80 (R = Me) of 85%. A chiral enamine moiety was hence shown to have a stronger influence on the asymmetric induction compared to a chiral ester group174. To obtain maximum effect the concept of double stereodifferentiation175 was employed. That is, the chiral enamine (81 X = CH2, S) was alkylated with a chiral ester [78 R = ( + )-menthyl]. In this case the reaction proceeded with complete diastereoselectivity and complete enantioselectivity (de = ee 99.9%), and gave the pure products (l S, 2R)-80 [R = ( — )-menthyl, X = CH2] and (l R, 2R)-80 [R = ( + )-men-thyl, X = S] in quantitative yield174. 

Since the mid-1970s, Enders and co-workers have demonstrated the powerful abilities of (5)-2-methoxymethylpyrrolidine (SMP) and its (/J)-enantiomer (RMP) as notable chiral auxiliaries. Numerous applications to s)unmetric synthesis using commercially available SMP and RMP have been appeared in the literatures [74,75,76]. In addition to the brilliant success of the worldwide-recognized chiral auxiliaries, the Enders group has also explored the utilization of sugar-based chiral auxiliaries since the start of the twenty-first century. The Enders group is predominantly concerned with diacetone-D-hexofuranoses as chiral templates. 

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., Kipphardt, H. Asymmetric synthesis. (S)-2-methoxymethylpyrrolidine - a chiral auxiliary. Nachrichten aus Chemie, Technik und Laboratorium 1985, 33, 882-888. 

Tin-lithium exchanges. A method for the preparation of a-hydroxy boronic esters takes advantage of the facile Sn/Li exchange of a-stannylalkyl MOM ethers. Subsequent reaction of the lithioalkyl ethers with boronic esters displaces one of the alkoxy groups of the latter." The reaction of chiral A-tributylstannylmethyl-2-methoxymethylpyrrolidine with BuLi and then aldehydes gives diastereomeric mixtures of P-amino alcohols. ... 

The Diels-Alder chemistry of chiral amino-1,3-butadienes has recently been reviewed and has been the subject of several studies since. For instance, Enders and Klatt studied the reactions between chiral diene 305 carrying (5)-2-methoxymethylpyrrolidine as... 

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. 

Silylation of azaallyllithium reagents derived from hydrazones unlike silylation of enolates seems to occur mainly on cartwn. While chiral (S)-l-amino-2-methoxymethylpyrrolidine (SAMP) aldehyde hydrazones (c/. equation 4) alkylate to a greater extent on nitrogen to form an azaallylsilyl reagent, ketones give predominant C-silylation. In the case of chiral ketone hydrazones derived from (5)-(4), a-silylated ketone hydrazones are produced in these reactions with consistently high ee ( 6%) ... 

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... 

Enders s chiral hydrazones 53 have also been employed to address the problem of asymmetric synthesis.31 His (5)-l-amino-2-methoxymethylpyrrolidine (SAMP) exhibits the ability to control the diastereoselective addition of TMSCN to chiral hydrazones 53 that gave rise to chiral a-aminonitriles 54. 

Conjugate additions. The Yb(OTf)3-catalyzed addition of a chiral V-amino-2-methoxymethylpyrrolidine to alkenyl sulfones is crucial to a process for the synthesis of optically active p-sulfonylamines. ... 

Enolates with Chiral Auxiliaries. Enantioselective alkylation of carbonyl derivatives encompassing chiral auxiliaries constitutes an important synthetic process. The anions derived from aldehydes, acyclic ketones, and cyclic ketones with (S)-l-Amino-2-methoxymethylpyrrolidine (SAMP) are used to obtain alkylated products in good to excellent yields and high enan-tioselectivity (e.g. eq 21). ... 

Acylhydrazones, R CH=N-NHCOR , undergo stereoselective Mannich reactions with silyl ketene acetals to give j8-hydrazido esters, using activation by a chiral silicon Lewis acid. Alternatively, the use of silyl ketene imine gives a /3-hydrazido nitrile. Enantioselective (5)-l-amino-2-methoxymethylpyrrolidine (SAMP) hydrazone alkylation of aldehydes and ketones is the subject of a computational study, providing a useful screening method for possible new candidates. " ... 

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... 

One of the most successful classes of chiral auxiliaries for asymmetric synthesis is that of Enders proline-based hydrazines, namely (S)-l-amino-2-methoxymethylpyrrolidine (SAMP, 74) and its (R)-enantiomer RAMP (Scheme 11.11) [68]. Enders has reported that chiral hydrazones such as 75 undergo diastereoselective additions with organolithium reagents. The facile removal of the auxiliary by reductive cleavage of the N-N bond enables it as a versatile tool for the synthesis of a wide range of chiral secondary amines [69, 70]. As shown in Scheme 11.11, the secondary amine 77 was thus prepared in 73 % overall yield and 93 % ee [69]. 

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