Prolinol methyl ether

The second method is based on the optically active enamine formed from (S)-prolinol methyl ether and cyclohexanone. This enamine reacts spontaneously with 2-(arylmethylcnc)propane-dioates to give, after hydrolysis, the 2- (.S )-aryl[(,S )-2-oxocyclohexyllmethyl propanedioates 4 in 35-76% yield with d.r. 94 6 > 97 361. 

Examples of such three-carbon synthons are 2-nitro-2-propen-l-yl acetates and piva-lates, which have been developed by Seebach and coworkers57,58 as reagents for [3 + 3] cyclizations with cyclic and acyclic ketone enamines. After workup these reactions give 4-nitrocyclohexanones. With enamines from prolinol methyl ether and cyclic ketones, enantiomerically pure compounds were obtained58. An example of such a [3 + 3] cyclization is the synthesis of bicyclic nitroketone 99 from nitroallylic ester 97 and enamine 98 (equation 18). 

Prolinol methyl ether 31 is used in Enders s SAMP and RAMP chiral auxiliaries (chapter 27) and (S)-()-SAMP 32 can be made in 50-58% overall yield from (S)-L-(—) -proline on a 75 g scale.12... 

Our synthesis of (5,)-(+)-polyzonimine (69) is summarized in Figure 3.18.52,53 Commercially available 2-methylcyclohexanone A was converted to aldehyde B. This was treated with (S)-prolinol methyl ether... 

Reactions of the enamine derived from cyclohexanone and prolinol methyl ether with /(-nitrostyrenes have been described by Seebach and co-workers (Scheme 20, Table 6) (33,44). This procedure uniformly provides the syn diastereomer as the exclusive detectable product. With the exception of the 2-bromo-/ -nitrostyrene in entry 4, enantiomeric excesses of > 92% are observed. 

Propargylic alcohols can be synthesized by alkylation of silylmethylacetylenes and oxidative desilylation. This reaction is rendered enantioselective by anchoring he silyl group to a prolinol methyl ether."... 

A DKR of a 5-hydroxytricyclodecadienone using (S)-prolinol or its methyl ether as the chiral mediator led to the corresponding enaminones. This approach, which constituted an asymmetric desymmetrisation of a Diels Alder... 

In another example, the aiylation of ketone enolates was achieved indirectly via an intermolecular Heck reaction. In this case, the diastereoselectivity is induced by chelation of a metal-coordinating auxiliary. The inexpensive and commercially available amino alcohol (6()-l-methyl-2-pyrrolidine-methanol was selected as a suitable chiral auxiliary (Scheme 13.47). The prolinol vinyl ether 182 was... 

Proline and proline derivatives have been utilized extensively as chiral catalysts for a wide range of asymmetric transformations [40, 132]. Gelman has documented a remarkable case in which enolizable aldehydes undergo selective Michael additions to enone acceptors (Equation 28) [133]. Diphenylpro-linol methyl ether (165) proved superior to other prolinol derivatives in terms of enantioselectivity and reactivity. As an example, the addition of oc-tanal (163) to ethyl vinyl ketone (164) in the presence of 5 mol% of 165 was carried out without solvent to furnish 166 in 87% yield and >95% ee. 

General procedure for the production of Boc-protected a,a-diaryl-L-prolinols (6). To 100 mL of a 0.42 M solution of ArMgBr in THF (0.042 mol) at 0°C was added N- t- BOC)-L-proline methyl ester (5) (3.0 mL, 0.014 mol) dropwise via syringe over a five-minute period. The solution was stirred for at least 4 h at 25°C and then cooled to 0°C. After slow addition of 3 mL of water, the solution was slowly warmed to ft with stirring. The mixture was decanted and the solid was washed with 100 mL of ethyl ether. The organics were pooled and washed with brine, dried with sodium sulfate and evaporated to yield the final compound. 

The chiral auxiliary can be recycled, since methanolysis of the 1-alkylated 3-trimethylsilyl-2-propynamines regenerated prolinol ether, a precursor of (S)-l-[(dimethoxy)methyl]-2-(meth-Oxymethyl)pyrrolidine. 

Scheme 8). Conjugate addition of the resulting enamine-silyl ether to methyl a-trimethylsilylvinyl ketone in the presence of MgCl2 provided the cyclohex-enones. Using the prolinol-derived enamine, the annelated product was obtained with 77% ee.

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