Lithiation-Induced Migrations from Nitrogen to Carbon in Terminal Aziridines

Link: http://www3.interscience.wiley.com/cgi-bin/abstract/114122819/ABSTRACT

From Prof. David M. Hodgson's group at University of Oxford, UK

A nice method involving a 1,2-anionic migration of Boc and phosphonate groups upon deprotonation with LiTMP of terminal N-Boc and N-phosphonate aziridines, respectively, was recently reported in ACIEE. This was done in comparison to their earlier study of deprotonation and trapping with external electrophile of the terminal N-Bus (Bus = tert-butylsulfonyl) aziridine.

In comparison, when the N-Bus aziridine was deprotonated and quenched with CD3OD, aziridine 3 was obtained. But when N-Boc aziridine was employed, only 4a was isolated along with 50% of recovered SM without deuterium incorporation.

The reaction was investigated further and a satisfying condition set was identified (3 equiv of LiTMP at -78 C). The scope of the methodology was then investigated and the results are summarized below.

From the table, the followings are the notable points:

- Complications were not observed from potential allylic deprotonation, cyclopropanation, or benzylic deprotonation (entries 2 and 3)

- X-ray crystallographic analysis of 4c supported the assigned trans stereochemistry

- Distal and proximal protected alcohols were tolerated (entries 4 and 5)

- A potentially eliminable primary chloride was also tolerated (entry 6)

- A 2,2,3-trisubstituted aziridinylester could also be accessed (entry 7), although in this case warming to 0 C was required for reaction to occur.
- No degradation of ee was observed under the reaction conditions (entry 8, determined by chiral HPLC analysis of the 2,4-dinitrobenzoyl derivatives)

Also, attempted reaction of a 2,3-disubstituted aziridine (N-Boc aziridine of cyclohexene) only led to return of starting material, presumably owing to unfavorable steric interactions. When the latter reaction mixture was allowed to warm from -78 C to 0 C, a mixture of starting material and decomposed material was obtained, whereas warming to room temperature resulted in only decomposition.

A crossover experiment was conducted and the anionic migration was found to occur in the intramolecular fashion (hence 1,2-migration).

One of the products obtained from the 1,2-migration of Boc group was further utilized in a number of useful subsequent transformations. These include:

- Regioselective hydrogenolysis of 4b to give protected beta-amino acid 8
- Oxidative cycloamination of the tethered olefin of 4b with NBS to give azabicycle 9, followed by subsequent elimination using DBU to give enamine 10
- Regioselective Swern oxidation of 4b, which occurred in a completely regioselective manner to give azirine 11

The utility of this methodology was further demonstrated in the scheme below in a concise asymmetric synthesis of a stable ester of the unstable antibiotic natural product azirinomycin 12. Note that compound 13 was obtained in more than 99% ee.

1,2-Phosphonate migration of terminal N-phosphonate aziridine was then investigated and a new condition set was established for this substrate (5 equiv LiTMP at -78 C, high dilution). The scope of this reaction was subsequently studied and the results are summarized in the table below. It should be noted that the 1,2-N-to-C migration reaction of N-phosphonate aziridine derivatives shows a similar selectivity profile to that of the N-Boc derivatives.

Utility of one of the phosphonate products was further demonstrated in the hydrogenolytic ring cleavage of (-)-19h to give beta-aminophosphonate (+)-20 in 68% yield. Beta-Amino-phosphonates and the corresponding phosphonic acids have attracted considerable interest as replacements for natural amino acids in various targets of medicinal interest.