N-Boc-pyrrolidine

Campos, K.R., Klapers, A., Waldman, J.H., Dormer, P.G., Chen, C.Y. (2006) Enantioselective, Palladium-Catalyzed a-Arylation of N-Boc-pyrrolidine. Journal of the American Chemical Society, 128, 3538-3539. 

We became interested in a disconnection between the pyrrolidine and the aryl group (Approach D) as the most convergent method for enantioselective construction of 12 [10]. Although (-)-sparteine mediated enantioselective lithiation of N-Boc pyrrolidine 19 is well established by Beak [11], arylation of the resulting chiral... 

Scheme 8.11 Enantioselective coupling of N-Boc pyrrolidine with aryl bromide 3.

The key to the success of the synthesis was the development of a novel method for enantioselective formation of a-arylpyrrolidines. In this method, (-)-sparteine-mediated, enantioselective lithiation of N-Boc-pyrrolidine 19 was followed by an in situ transmetallation to zinc and Pd-catalyzed coupling reaction with aryl bromide 3, which afforded 2-arylpyrrolidine in 63% isolated yield and 92% ee. Notably, the acidic aniline NH2 group was tolerated under the coupling reaction conditions. 

Having demonstrated a practical and reliable method to access 2-arylpyrrolidines in high enantioselectivity, we felt that a noteworthy extension of this methodology would lie in its application to bis-arylated products 27, providing a rapid and efficient approach to enantiopure C2-symmetric 2,5-diarylpyrrolidines, which have been identified as valuable chiral auxiliaries and chiral ligand manifolds [29]. Towards this end, substrate 26a was subjected to the standard arylation conditions, which produced 2,5-diphenyl-N-Boc-pyrrolidine 27 in a 96 4 diastereomeric ratio, and 57% isolated yield (s-BuIi/TMEDA produced 27 in lower d.r. (66 34) and yield (42%)), as depicted in Scheme 8.13. 

Although impurities generated in the coupling of N-Boc pyrrolidine and aryl bromide 3 were cleanly rejected during crystallization of 5 and, therefore, did not affect the quality of the product, we decided to isolate and identify these impurities for better understanding of the coupling reaction (Scheme 8.14). The debromi-nated compound 28 was observed at a very low level (<1%). The enamide impurity... 

Even though it is difficult to achieve a C-H insertion at methylene sites a to an N-Boc group in acyclic systems, many cyclic amines are excellent substrates for the C-H insertion. The reaction with N-Boc-pyrrolidine (31) is a spectacular example [27]. The Rh2(S-DOSP)4-catalyzed reaction of methyl phenyldiazo-acetate with 31 at -50 °C generates the C-H insertion product 32 in 94% ee and 92% de [Eq. (16)]. 

The reaction with N-Boc-pyrrolidine may be taken a step further by inducing a double C-H insertion sequence [27]. This results in the formation of the elaborate C2-symmetric amine 35 as a single diastereomer with control of stereochemistry at four stereogenic centers. The enantiomeric purity of 35 is higher than that obtained for the single C-H insertion products, presumably because kinetic resolution is occurring in the second C-H insertion step. 

B. (R)-(+)-2-(Diphenythydroxymethyl)-N-(tert-butoxycarbonyl)pyrrolidine. An oven-dried, 2-L, three-necked flask, equipped with a magnetic stirring bar and a thermocouple (Note 4), is charged with (-)-sparteine (30.2 mL, 131 mmol) (Note 5), N-Boc-pyrrolidine (15.0 g, 67.6 mmol), and anhydrous ether (900 mL) (Note 6). The solution is cooled to -70°C (dry ice/acetone bath) (Note 4). To this solution is added sec-butyllithium (96 mL, 1.16 M in cyclohexane, 111 mmol) (Notes 7 and 8) dropwise over a period of 35 min (Note 9). The reaction is then stirred at -70°C for 5.5 hr (Note 10). 

Intramolecular enantiosituselectivity is exemplified by the biosynthetic formation of the mustard oil glucoside sinigrin (60) in horseradish, " the deprotonation of N-Boc-pyrrolidine (62) with sec-butyllithium (s-BuLi)/(-)-sparteine, followed by methylation, "" and, the oxidation of enol 64. Intermolecular enantiosituselective transformations are exemplified by the hydrolysis of racemic N-dodecanoylphenylalanine p-nitrophenyl esters (( )-67) in the presence of tripeptide catalyst (Z)-L-Phe-L-His-L-Leu (68) in each of the latter two cases, only one (externally) enantiotopic carbonyl reacts preferentially. It should be pointed out parenthetically, that as a result of the enantiosituselectivity in these transformations, one has, in effect, kinetic resolution of ( )-67. The electron-impact induced elimination in acetate 71, and the oxidation of 73 exemplify intramolecular diastereosituselective transformations. The epoxidation of the mixture 76/77 is an example of an intermolecular diastereosituselective process at the same time that each substrate is subject to enantiositunonselectivity of the carbonyl sub-sites. 

Kozlowski has studied lithiation of N-Boc pyrrolidine (cf. Scheme 16) using racemic 1,5-diaza-c/s-decalins (e.g., 36 and 37, Fig. 3), and found that for 36 the ligands with the smallest most electron rich R groups (Me>Et>CH2f-Bu>CH2CF3 Bn) were most effective [74, 75]. The ready availability of both... 

An interesting feature of the C2 character of N-Boc-pyrrolidine is that sequential substitution by the same electrophile leads to significant improvement in... 

Efforts to extend the direct asymmetric lithiation and substitution from N-Boc-pyrrolidine to AT-Boc-piperidine have not been successful. Although a low yield of an enantioenriched product can be obtained from N-Boc-piperidine, competing reactions intervene, a result which is consistent with calculations [41]. 

Alkyllithiums are sufficiently strong as bases to remove the protons adjacent to the nitrogen atom of N-Boc pyrrolidine, shown in the margin. The product of deprotonation is an organo-lithium which is a chiral molecule the lithium-bearing carbon is chiral. 

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