Bis methoxymethyl pyrrolidine

Handling, Storage, and Precautions irritant use only in a fume hood. 

Chiral Amines with C2 Symmetry, trans-2,5-Dimethylpyrrolidine (1) was the first chiral amine possessing C2 symmetry used as a chiral auxiliary in asymmetric synthesis. Since that time a number of related systems have been developed including the title compound (2) and (4). These amines were developed as C2-symmetric analogs to the commercially available prolinol derivative (5). While proline-derived chiral auxiliaries have been widely used in asymmetric synthesis, the C2-symmetric chiral auxiliaries often give enhanced stereoselectivity when compared directly to the prolinol derivatives. Unfortunately the preparation of the C2-symmetric compounds is more tedious and, at the time of writing, none are commercially available. For example, the standard route to chiral pyrrolidines (2) and (3) involves the resolution of tranf-N-benzylpyrrolidine-2,5-dicarboxylic acid, although other preparations have been 

A list of General Abbreviations appears on the front Endpapers 

Reduction of a- and p-Ketoamides Derived from C2-Synunetric Pyrrolidines. By analogy to the alkylation reaction discussed above, acylation of the enolate derived from amide (8) produces the p-ketoamide (11) as a single diastereomer (eq 3).  

Subsequent reduction of the ketone produces either the syn or anft p-hydroxyamides with high diastereoselectivity (eqs 4 and 5). Pyrrolidine-derived a-ketoamides have also been shown to react stereospecifically with reducing agents, as well as with other organometallic reagents.  

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The asymmetric synthesis of 1,2-diamines using (2S,3f ,4f ,5,S )-l-ami no-3,4-dimethoxy-2,5-bis(methoxymethyl)pyrrolidine with high enantiomeric excess (93-96% ee) has been developed, as in Eq. 4.27.33... 

Table 7. 2-Alkylalkanoic Acids by Alkylation of Enolates from (2R,5R)-1-Acyl-2,5-bis(methoxymethyl)pyrrolidines, Followed by Hydrolysis7...

The corresponding methyl ethers, i.e., alkylated rranj-1-acyl-2,5-bis(methoxymethyl)pyrrolidines 1 (R3 = CH,). are first demethylated by trichloroborane in CH,C12 prior to the acidic hydrolysis (see Tabic l)1. 

The iodolactonization of amides containing (2/ ,5/ )-bis(methoxymethyl)pyrrolidine as a chiral auxiliary38 gives high enantiomeric excesses through diastereotopic alkene differentiation, as well as face differentiation. Thus, treatment of amide 5 with iodine in tetrahydrofuran under kinetic conditions affords the 2,4-tra/w-disubstituted lactone in 54% yield and 91%ee, as determined by H NMR with Eu(hfc)3. 

Related Reagents. (5)-l-Amino-2-methoxymethylpyrroli-dine fra/w-2,5-Bis(methoxymethyl)pyrrolidine 10,2-Cam-phorsultam 10-Dicyclohexylsulfonamidoisobomeol a-Me-thyltoluene-2,a-sultam (35,cw)-Tetrahydro-3-isopropyl-7a-methylpyiTolol[2,l-l>]oxazol-5(6/f)- one. 

Related Reagents. (S)-l-Amino-2-methoxymethylpyrroli-dine rrani-2,5-Bis(methoxymethyl)pyrrolidine 10,2-Camphor-... 

Comparable results are obtained in radical additions to several C2-symmetric fumaric bisamidcs. 2,5-Dimcthylpyrrolidine14,15,2°, 2,5-bis(methoxymethyl)pyrrolidine and 1,3 4,6-di-0-benzylidene-2,5-dideoxy-2,5-imino-L-idit21 are used as chiral auxiliaries. Reactions with cyclohexyl or tort-butyl radicals, generated by the mercury or the tin method, respectively, proceed with high levels of asymmetric induction, yielding essentially only one of the two possible products. 

The ability of DAST (1) to replace hydroxy groups of alcohols with fluorine was discovered by Middleton. Many dialkylaminosulfur trifluorides, differing from DAST (1) only by the amino substituent, as well as bis(dialkylamino)sulfur difluorides have been prepared (for a recent review, see ref 38). but none has become as popular as DAST. This is due to the fact that DAST was the first to be commercially available, although its high cost may be prohibitive for industrial applications in most cases. Recently, a homochiral aminofluoro-A -sulfanc, [(5)-2-(methoxymethyl)pyrrolidin-l-yl]sulfur trifluoride, was synthesized. In the reaction of this DAST analog with racemic silylated alcohols, only low to moderate enantiomeric excesses of fluorinated products have been observed. ... 

In this latter structure, roughly depicted as (154), there are two different lithium atoms as well as two different anion residues. In one of the residues a lithium is -coordinated and in the other residue the lithium is T) -coordinated. Hie possible origins of the selectivity of the alkylations of the metallated hydiazones are discussed relative to this structure. Hie lithiated hydrazone enolate (155) prepared from (S)-(-)-l-amino-2-(methoxymethyl)pyrrolidine (SAMP) hydrazone of 2-acetylnaphthalene (156) yields the monomeric bis-THF-solvated species (157) as ruby red crystals. Hiis is one of the few examples of the crystallization of a resolved enolate substrate. ... 

Many chiral auxiliaries are derived from 1,2-amino alcohols [7], including oxazolidinones (1) [7-9], oxazolines (2) [10,11], bis-oxazolines (3) [12,13], oxa-zinones (4) [14], and oxazaborolidines (5) [15-17]. Even the 1,2-amino alcohol itself can be used as a chiral auxiliary [18-22]. Other chiral auxiliary examples include camphorsultams (6) [23], piperazinediones (7) [24], (S)-l-amino-2-(methoxymethyl)-pyrrolidine (SAMP) (8) and (R)-l-amino-2-(methoxymethyl)-pyrrolidine (RAMP) [25], chiral boranes such as isopinocampheylborane (9) [26], and tartaric acid esters (10). Some of these auxiliaries have been used as ligands... 

The formation of the methoxymethyl ether (MOM) is achieved by conventional techniques (chloromcthyl methyl ether/Afi.V-diisopropylethylamine) analogously, the methyl ether is obtained by reaction with NaH/ iodomethanc35. The, V-benzyl group is finally removed with Pd-C H,. Thus. (25.55)-2.5-bis-(inethoxymethoxymethyl)pyrrolidine is obtained yield 3.1 g (66%). 

N,N-Disilylhydrazines. (S)-(-)-l-Amino-2-(methoxymethyl)pyrrolidine in THF added at 0° under N2 to KH powder, stirred for 1 h, the suspension warmed to room temp., HMPA and ca. 2 eqs. hexamethyldisilane added, stirring continued for 24 h, and quenched with water - (S)-l-bis(trimethylsilyl)amino-2-(methoxymethyl)pyrrolidine. Y 94%. F.e., incl. N,N,N -trisilylhydrazines and tetrakis(trimethylsilyl)hydrazine, s. J.R. Hwu, N. Wang, Tetrahedron 44, 4181-96 (1988). 

Pr, n-Propyl Py, Pyridine PROPHOS, 1,2-Bis(diphenylphosphino)propane PTA, l,3,5-Triaza-7-phosphaadamantane PTC, Phase-transfer catalyst PTSA, p-Toluenesulfonic acid R, An organic group RAMP, R-(+)-Amino-2-(methoxymethyl)pyrrolidine Rf, Perfluoroalkyl... 

Amines (S)-1 -Amino-2-methoxymethyl-1 -pyrrolidine. Azidomethyl phenyl sulfide. Bis(methoxycarbonyl)sulfur diimide. N,N-Bis(trimethylsilyl)rnethoxymethylamine. 

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