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. 

As another extension of this process, Davies et al. have developed highly regio-, diastereo- and enantioselective C-H insertions of methyl aryldiazoace-tates into cyclic A-Boc-protected amines catalysed by rhodium(II) S)-N- p-dodecylphenyl)sulfonylprolinate. The best results were obtained in the case of the C-H insertion of methyl aryldiazoacetates into A-Boc-pyrrolidine, which gave, in all cases, a diastereoselectivity and an enantioselectivity greater than 90% de and 90% ee respectively (Scheme 10.77). The synthetic utility of this method was demonstrated by means of a two-step asymmetric synthesis of a novel class of C2-symmetric amines. 

Scheme 10.77 Rh-catalysed intermolecular C-H insertions of methyl aryldiazoacetates into A-Boc-pyrrolidines with sulfonamide ligand.

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... 

Treatment of methyl bromozincacetate with VV-(Boc)pyrrolidine-2-thione affords good yield of vinylogous carbamate (Scheme 35).74... 

Use of aryl, vinyl and alkynyl iodides as electrophiles is possible using Pd° catalysis. Dieter and Li have evaluated the reaction between Al-Boc-pyrrolidine and Af-Boc-piperidine with several aryl and heteroaryl iodides, 1- and 2-iodo-l-hexene, and 1-iodohexyne. The yields range from about 10-80%, with typical yields in the 40-60% range (Scheme 32). 

The small number of electrophiles that react well with Af-Boc-2-hthiopyrrolidine limits applications of the asymmetric deprotonation of Af-Boc-pyrrolidine. In a significant development. Dieter and coworkers have shown that transmetalation of the enantioen-riched 2-lithiopyrrolidine with CuCN-2LiCl forms a cuprate that reacts enantioselectively with vinyl and allenyl iodides (Scheme 34). Enantioselectivities in the 90-95% range were achieved, although the reaction is very sensitive to reagent purity. ... 

The first successful examples for asymmetric deprotonation by alkyllithium/(—)-sparte-ine (11) utilizing O-allyl and O-alkyl carbamates were published in 1989-1990 by Hoppe and coworkers °. Later, in 1991, Kerrick and Beak contributed the application of this method to Ai-Boc-pyrrolidine" (Sections II.D.l). 

Astonishingly enough, enantioenriched lithiated cyclooctene oxides 142, originating from (—)-sparteine-mediated lithiation of 124 by i-BuLi/(—)-sparteine (11), could be trapped by external electrophiles, resulting in substituted epoxides 143 (equation 31) ° . Again, the use of i-PrLi furnished better enantioselectivities (approx. 90 10). Lithiated epoxides, derived from tetrahydrofurans and A-Boc-pyrrolidines, undergo an interesting elimination reaction . ... 

As Beak and coworkers have established several years ago, A-rert-butoxycarbonyla-mines are sufficiently acidic to be deprotonated adjacent to the nitrogen atom . When applying 5-BuLi/(—(-sparteine (11) to A-Boc-pyrrolidine, asymmetric deprotonation (149), onepro-S-H is removed with high selectivity, furnishing the configurationally stable 2-lithio derivative 150 which was trapped with several electrophiles to form the optically active substitution products 151 (equation 33) A prescription in Organic Syntheses is... 

To 1.2 equiv (0.25 M) of (-)-sparteine in diethyl ether are added 1.2 equiv of j-BuLi, the mixture is stirred for 15 min and transferred at — 78 °C to a solution of 1 equiv of (fm-butoxycarbonyl)pyrrolidine in diethyl ether at — 78CC. After 4h the mixture is added to 1.5 equiv of a precooled ( — 78 X) solution of the alkylation reagent in diethyl ether, and then allowed to warm slowly to 20 °C over 3 h. The 2-substiluted Boc-pyrrolidines are purified by flash chromatography (ethyl acetate/hexane). 

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. 

Fmoc-4-terI-butyloxycarbonylaminophenylalanine, Fmoc-4-benzoylpheny-lalanine, Fmoc-D-tetrahydroisoquinoline-3-COOH, Fmoc-thiazolidine-4-carboxylic acid, Fmoc-D-propargylglycine, Fmoc-3-(2-naphthyl)alanine, Fmoc-D-3-(2-naphthyl)alanine, Fmoc-3-aminobenzoic acid, (25,45) Fmoc-4-amino-l-Boc-pyrrolidine-2-carboxylic acid, (d stands for d configuration.)... 

To assess the effect of intramolecular chelation in this class of organolithium, Gawley also made 157 and treated it under similar conditions.57 In THF alone, the MEM-protected 158 has greater chemical stability than 155, and is configurationally stable up to about -60 °C. Like the lithiated Boc-pyrrolidine 138 (but unlike the lithiated /V-methyl pyrrolidines 155) TMEDA tends to decrease its configurational stability and a direct comparison between MEM protected 158 and 155 in the presence of TMEDA shows that the MEM group also... 

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