Methyl -prolinate

A. K. Beck, S. Blank, K. Job, 0. Seebach, and Th. Sommerfeld 62 SYNTHESIS OF (S)-2-METHYL-PROLINE A GENERAL METHOD FOR THE PREPARATION OF o-BRANCHED AMINO ACIDS... 

Probably the most recently discovered natural product of this class is FR235 222 (65) [79], a potent HDACi vith IC50 = 17nM. This compound differs from some of the other members of the class due to the isovaline and methyl proline moieties, although more markedly contains a a-hydoxyketone I-Ahoda amino acid as a zincchelating moiety. 

One drawback for the direct organocatalytic a-oxidation of aldehydes and ketones is the use of nitrosobenzene, which is an expensive oxygen source . This has led to further investigations in order be able to use other oxidants. Recently, Cordova et al. [20] reported that r-a-methyl proline could incorporate O2 in the a-position of an aldehyde. The presence of tetraphenylporphyrin (TPP) as sensitizer was necessary to promote the formation of singlet 02 as the electrophilic species. Although, the enantioselectivities obtained were only moderate (54-66% ee), this represents undoubtedly a very intriguing alternative to the use of nitrosobenzene in this type of reaction. 

According to Eq. (11), Confalone has presented a new method of generation of azomethine ylides through the condensation of N-substituted ot-amino esters with aldehydes (83JOC2994 84JA7175). Thus, 5-formylmethyldibenzo-[a.d]tropylidene or o-(allyloxy)benzaldehyde is heated with ethyl sarcosinate or methyl prolinate under reflux in toluene. The water formed is continuously driven off with the aid of a Dean-Stark trap. The ester-stabilized azomethine ylide 77 or 78 quantitatively generated is trapped in an intramolecular fashion. 

A Sml2-promoted reductive deamination of methyl prolinate derivative 235 to a 5-aminoester, followed by spontaneous recyclization to lactam 236, was exploited in the synthesis of several lupine alkaloids (Scheme 69) <05JOC499>. 

Unnatural N-aryl dipeptides can be easily obtained using our procedure direct acylation of a-aminoacid esters with nitro-benzoyl chlorides followed by reductive alkylation leads to the preparation of derivatives of methyl prolinate 1 and methyl valinate 2 (Table 3). A small but significant diastereoisomeric excess (d.e.) of 20-30% is measured by NMR. Optimisation of the reaction conditions as well as of the nature of the inductor may generate better d.e.. These... 

In one of the first reported stereoselective alkylation reactions [18], Yamada described the use of a methyl prolinate as chiral auxiliary in the methylation of a cyclohexanone-derived enamine (Fig. 3 reaction D).The low stereoselectivity of the reaction clearly depends on the possibility for the alkylation to occur on a different conformation of the enamine, namely the one in which the C-C double bond is transoid to the stereocenter, that thus cannot exert any useful stereocontrol. 

Neoefrapeptins, neoefrapeptin A Ac-Pip-Aib- Pip- Iva-Aib- Leu-/3 -Ala-Gly-Acc-Aib-Pip-Gly-Leu-Iva-aX, a group of peptides with insecticidal activity isolated from the fungus Geotrichum candidum. AU 12 neoefrapeptins (A-I, L-N) contain the very rare amino acid 1-amino-cyclopropane-carboxylic acid (Acc), and some of them (F, I, L, M) also contain (2S,3S)-3-methyl-proline instead of pipecolic acid (Pip) in position 11. Further unusual building blocks are isovaline (Iva) and the C-terminal amide moiety X = 2,3,4,6,7,8-hexahydro-l-pyrrolo [ 1,2-a]pyrimidine. Neoefrapeptins show a close sequence similarity to the efrapeptins [A. Fredenhagen et al., J. Antibiot. 2006, 59, 2006]. 

RB=NR and alkynes <20040M5048>. The structure and stereochemistry of the novel bora derivatives of T[(2-hydroxy-l-naphthyl)methyl]proline were elucidated by means of two-dimensional nuclear magnetic resonance (2-D NMR) spectra as well as AMI semi-empirical calculations <2005TA2019>. 

While in principle many different substituents may be introduced stereoselectively using this methodology, only (S)-a-2-methyl-proline (7a, R = CH3) and derivatives have been applied in organocatalytic transformations. 

In 2001 Barbas III et al. reported the amino acid-catalysed direct asymmetric aldol reaction between ketones and aldehydes. Using the benchmark condensation reaction between acetone and p-nitro-benzalde-hyde, the authors tested many different amino acids as organocatalysts, including (5 )-ot-2-methyl-proline 7a (Scheme 11.2). In this reaction however 7a proved to be much less reactive than (S)-proline (1), as well as slightly less enantioselective. Compound 7a was also found to be less efficient than 1 in the direct organocatalytic asymmetric a-oxidation of cyclohexanone with iodosobenzene, as reported by Cordova et ah in 2005 (Scheme 11.3). ... 

Scheme 11.3 Direct organocatatytic as5mnmetric a-oxidations of cyclohexanone with iodosobenzene catatysed by (S )-proline (1) and (S )-a-2-methyl-proline (7a).

Although no detailed mechanistic rationale was elucidated, the remarkable increase in enantioselectivity obtained by switching from (5 )-proline 1 to (5 )-a-2-methyl-proline 7a was ascribed to the higher steric congestion at the a-geminal carbon of 7a, that favours the a h -enamine (Figure 11.3). 

More interesting, is that the use of (5)-a-methyl proline 98 significantly improved both the yield and importantly - the enantioselectivity. It is postulated that this improvement is due to the effect of the a-methyl substituent on the geometry of the resulting enamine (favouring the anti-conformation instead of the 1,3-allylically strained 5yn-conformation - Scheme 1.23). 

Dodecahydro-6,9-bis(methylene)-2-oxoazuleno[4,5-Z>]furan-3-yl]methyl]proline,... 

SCHEME 2.2. Catalysis of the intramolecular aldol reaction by proline, proline methyl ester, and A -methyl proline. 

In 2004, Vignola and List [111] demonstrated the ability of proline-derived catalysts to overcome drawbacks associated with the stoichiometric alkylation of preformed aldehyde enolates when they described an elegant amino acid catalyzed intramolecular a-alkylation reaction of haloaldehydes. The reaction furnished substituted cyclopentanes, cyclopropanes, and pyrrolidines in good yields and good enantio-selectivities (Scheme 8.23), when commercially available (5)-a-methyl proline (LV) as catalyst was used. The presence of a stoichiometric amount of additional base (tertiary amine) was required, not only to trap the hydrogen halide produced in the reaction but also because it has also significant effect on the stereoselectivity of the C—C bond-formation process by stabilizing the ant/ -TS of the /ra 5-enamine intermediate. Nevertheless, an intermolecular version of the reaction remains still elusive, mainly because of the deactivation of the amine catalyst by A -alkylation with the alkyl halide [112]. 

Method 4. A photochemical cyclization is employed to produce an amidophenanthrene derivative, which is subsequently further cyclized. In a variation of this method, the amidophenanthrene is formed from the corresponding acid and methyl prolinate by dehydration with DCC (i5). 

The origin of the )8-methylproline moiety present in paraherquamide A and several congeners has recently been investigated. Examination of the absolute stereochemistry of paraherquamide A, which possesses the (S)-absolute stereochemistry at C-14, led Williams et al. to speculate that the methylated proline may be derived from L-isoleucine as opposed to proline and S-adenosylmethio-nine (SAM) and this possibility was experimentally tested in Penicillium felluta-num (ATCC 20841) as shown in Fig. 5 [39]. The position of incorporation in paraherquamide A was determined using NMR and the percentage of the labeled amino acid incorporated was also determined using NMR. 

These workers found that l-[ C]-L-tryptophan was incorporated as expected (2.5%) with the label at C-12. The methyl-[ C]-methionine was not incorporated in the )3-methyl-proline ring but rather only at C-29, the N-methyl position of the monoketopiperazine ring (0.6%). Feeding of 1-[ C]-L-isoleucine to Peni-... 

Fig. 5. Biosynthetic derivation of the )S-methyl proline moiety of paraherquamide A [39]...

Such energy calculations have also been performed on substituted prolines. We have considered the case of methyl prolines and hydroxyprolines. In a methylproline,... 

Figure 5 is the F—O plot for 2-methyl proline and Figure 6 shows the plots for 3-, 4-, and 5-methyl prolines. Nitrogen is kept planar trigonal with fixed bond angles t, ... 

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