Asymmetric Synthesis of 1‐(2‐Pyrrolyl)alkylamines by the Addition of Organometallic Reagents to Chiral 2‐Pyrroleimines

Abstract

The addition of organometallic (lithium, magnesium, zinc) reagents to 2‐pyrroleimines derived from (S)‐valinol and (S)‐phenylglycinol gave N‐substituted‐1‐(2‐pyrrolyl)alkylamines with high yields and diastereoselectivities. The (S,S)‐diastereomers were useful intermediates for the preparation of enantiopure 1‐[1‐(2‐pyrrolyl)alkyl]aziridines by routine cyclization of the β‐amino alcohol moiety and for the preparation of (S)‐N‐benzoyl 1‐[1‐(2‐pyrrolyl)alkyl]amines and their N‐substituted derivatives by oxidative cleavage of the chiral auxiliary. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Mitsunobu and Related Reactions: Advances and Applications

“…1036 The authors have offered a possible rationalization based on the involvement of Et 3 N • HCl for these interesting results. Other examples involving aziridine formation pertain to the synthesis of (i) 2-(2-hydroxy-substituted) piperidine alkaloids, 1037 (ii) peptidomimetics via a N-2,4,6-trimethylphenylsulfonyl (Mts)-protected amino alcohol, 1038 (iii) pyrrolyl aziridines via the corresponding inactivated 1,2aminoalcohols, 1039 (iv) aziridine sulfides based on reduced (R)-cysteine, 1040 (v) nosyl-substituted aziridines derived from L-serine, 1041 (vi) exocyclic γ-aminoolefins, 1042 and (vii) tosyl aziridine-2-carboxylates. 1043 Direct formation of a lactam ring from 1,3-amino(amido) alcohols is fairly straightforward, and several examples of this type are known.…”

Asymmetric Synthesis of 8-Aminoindolizidine from Chiral 2-Pyrroleimines

“…The OH-free imines 8a,b were then treated with allylmagnesium chloride in excess amounts in anhydrous THF at 0 °C to give the known secondary homoallylic amines 9a,b. 8 Unexpectedly, in the first reaction run on the imine 8a, using only a slight exess of Grignard reagent (2.2 equiv), a 73:27 mixture of two isomeric amines were obtained, as evidenced by 1 H NMR analysis of the crude product. The major isomer was identified as the expected product 9a on the basis of the 1 H NMR spectrum, whereas the minor one 10a was supposed to have an isomerized propenyl substituent on the pyrrole nitrogen.…”

“…We started the investigation by routinely preparing in high yields the 1-allyl-2-pyrroleimines 8a and 8b from 1-allyl-2-pyrrolealdehyde by reaction with either ( S )-valinol and ( S )-phenylglycinol in dry dichloromethane in the presence of anhydrous magnesium sulfate (Scheme ). The OH-free imines 8a , b were then treated with allylmagnesium chloride in excess amounts in anhydrous THF at 0 °C to give the known secondary homoallylic amines 9a , b . Unexpectedly, in the first reaction run on the imine 8a , using only a slight exess of Grignard reagent (2.2 equiv), a 73:27 mixture of two isomeric amines were obtained, as evidenced by 1 H NMR analysis of the crude product.…”

“…Particularly, a five membered ring is formed by RCM when n = m = 0, thus leading ultimately to pyrrolizidines 1a , whereas to prepare indolizidines one has to build a six-membered ring in intermediate 2 by choosing n = 1, m = 0, or vice versa. All the routes appear viable at a first glance, as we have previously described the highly diastereoselective addition of various organometallic reagents to chiral 2-pyrrole imines derived from ( S )-valinol and ( S )-phenylglycinol, having either unprotected or trimethylsilyl-protected OH and NH functions …”

Asymmetric Henry reaction catalyzed by Cu(I)-based chiral amino alcohol complex

“…Then the residue was purified on silica gel column chromatography. Amino alcohols 5a 27 , 5c 28 , 5d 29 , and 5e 30…”